ijms-logo

Journal Browser

Journal Browser

Regulation by Non-coding RNAs

A topical collection in International Journal of Molecular Sciences (ISSN 1422-0067). This collection belongs to the section "Molecular Biology".

Viewed by 1005232
Printed Edition Available!
A printed edition of this Special Issue is available here.

Editor

Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Auenbruggerplatz 15, Austria
Interests: non-coding RNAs; microRNAs; cancer; inflammation; metabolism; gene expression; stem cells; epithelial-mesenchymal transition
* Non-Coding RNAs in Cancer: An Interview with Dr. Martin Pichler https://www.mdpi.com/1422-0067/17/4/605/htm

Topical Collection Information

Dear Colleagues,

Non-Coding RNAs are currently a hot research topic in many fields of biology, medicine, and chemistry. It is increasingly clear that non-coding RNAs are involved in fundamentally physiological and pathological processes. These processes touch on many important disciplines, from metabolism to cancer. Non-coding RNAs are regulative: they mainly influence biological processes by regulating other (protein-)coding gene expression. By doing this, the cellular properties of development and growth, stem cell regeneration, apoptosis, authophagy, etc., are strictly controlled by non-coding RNAs. This collection is dedicated to summarizing and highlighting the current research concerning the role of non-coding RNAs in regulating the aforementioned functions. The underlying mechanisms of action, the target molecules, the interactor pairs, and the pertinent cellular functions should all be presented. All relevant fields in medicine (with a special focus on metabolism, cancer, and inflammation) are of interest. The classes of non-coding RNAs should include microRNAs, other small non-coding RNAs, and long non-coding RNAs. Original research articles, review articles, and research letters are welcomed.

Dr. Martin Pichler
Collection Editor

Manuscript Submission Information

Manuscripts for the topical collection can be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on this website. The topical collection considers regular research articles, short communications and review articles. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page.

Please visit the Instructions for Authors page before submitting a manuscript. The article processing charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs).

Keywords

  • Regulatory RNA
  • sRNA
  • ncRNA
  • lncRNA
  • miRNA
  • siRNA
  • piRNA
  • CRISPR RNA
  • regulatory small RNA fragments

Related Special Issues

Published Papers (165 papers)

2023

Jump to: 2022, 2021, 2020, 2019, 2018, 2017, 2016, 2015, 2014

20 pages, 20046 KiB  
Article
Discovery of Salidroside as a Novel Non-Coding RNA Modulator to Delay Cellular Senescence and Promote BK-Dependent Apoptosis in Cerebrovascular Smooth Muscle Cells of Simulated Microgravity Rats
by Yiling Ge, Bin Zhang, Jibo Song, Qinglin Cao, Yingrui Bu, Peijie Li, Yungang Bai, Changbin Yang and Manjiang Xie
Int. J. Mol. Sci. 2023, 24(19), 14531; https://doi.org/10.3390/ijms241914531 - 26 Sep 2023
Cited by 1 | Viewed by 913
Abstract
Cardiovascular aging has been reported to accelerate in spaceflights, which is a great potential risk to astronauts’ health and performance. However, current exercise routines are not sufficient to reverse the adverse effects of microgravity exposure. Recently, salidroside (SAL), a valuable medicinal herb, has [...] Read more.
Cardiovascular aging has been reported to accelerate in spaceflights, which is a great potential risk to astronauts’ health and performance. However, current exercise routines are not sufficient to reverse the adverse effects of microgravity exposure. Recently, salidroside (SAL), a valuable medicinal herb, has been demonstrated to display an important role for prevention and treatment in cardiovascular and other diseases. In the present work, Sprague–Dawley rats with four-week tail-suspension hindlimb-unloading were used to simulate microgravity effects on the cardiovascular system. We found that intragastrical administration of SAL not only significantly decreased the expressions of senescence biomarkers, such as P65 and P16, but also obviously increased the expressions of BK-dependent apoptotic genes, including the large-conductance calcium-activated K+ channel (BK), Bax, Bcl-2, and cleaved caspase-3, in vascular smooth muscle cells (VSMCs) in vivo and in vitro. In addition, relative non-coding RNAs were screened, and a luciferase assay identified that SAL increased apoptosis by activating LncRNA-FLORPAR, inhibiting miR-193, and then triggering the activity of the BK-α subunit. Our work indicated that SAL is a novel non-coding RNA modulator for regulating the LncRNA-FLORPAR sponging miR-193 pathway, which significantly promoted BK-dependent apoptosis and delayed cerebrovascular aging-like remodeling during simulated microgravity exposure. Our findings may provide a new approach to prevent cardiovascular aging in future spaceflights. Full article
Show Figures

Graphical abstract

22 pages, 3799 KiB  
Article
A Novel Long Noncoding RNA in Osteocytes Regulates Bone Formation through the Wnt/β-Catenin Signaling Pathway
by Makoto Arai, Hiroki Ochi, Satoko Sunamura, Nobuaki Ito, Masaomi Nangaku, Shu Takeda and Shingo Sato
Int. J. Mol. Sci. 2023, 24(17), 13633; https://doi.org/10.3390/ijms241713633 - 04 Sep 2023
Viewed by 1058
Abstract
The vast majority of transcribed RNAs are noncoding RNAs. Among noncoding RNAs, long noncoding RNAs (lncRNAs), which contain hundreds to thousands of bases, have received attention in many fields. The vast majority of the constituent cells in bone tissue are osteocytes, but their [...] Read more.
The vast majority of transcribed RNAs are noncoding RNAs. Among noncoding RNAs, long noncoding RNAs (lncRNAs), which contain hundreds to thousands of bases, have received attention in many fields. The vast majority of the constituent cells in bone tissue are osteocytes, but their regulatory mechanisms are incompletely understood. Considering the wide range of potential contributions of lncRNAs to physiological processes and pathological conditions, we hypothesized that lncRNAs in osteocytes, which have not been reported, could be involved in bone metabolism. Here, we first isolated osteocytes from femurs of mice with osteocyte-specific GFP expression. Then, through RNA-sequencing, we identified osteocyte-specific lncRNAs and focused on a novel lncRNA, 9530026P05Rik (lncRNA953Rik), which strongly suppressed osteogenic differentiation. In the IDG-SW3 osteocyte line with lncRNA953Rik overexpression, the expression of Osterix and its downstream genes was reduced. RNA pull-down and subsequent LC-MS/MS analysis revealed that lncRNA953Rik bound the nuclear protein CCAR2. We demonstrated that CCAR2 promoted Wnt/β-catenin signaling and that lncRNA953Rik inhibited this pathway. lncRNA953Rik sequestered CCAR2 from HDAC1, leading to deacetylation of H3K27 in the Osterix promoter and consequent transcriptional downregulation of Osterix. This research is the first to clarify the role of a lncRNA in osteocytes. Our findings can pave the way for novel therapeutic options targeting lncRNAs in osteocytes to treat bone metabolic diseases such as osteoporosis. Full article
Show Figures

Figure 1

13 pages, 2636 KiB  
Article
LncRNA LINC02574 Inhibits Influenza A Virus Replication by Positively Regulating the Innate Immune Response
by Yanwei Zhang, Xiaojuan Chi, Jingyun Hu, Shulin Wang, Senhong Zhao, Yanan Mao, Benqun Peng, Ji-Long Chen and Song Wang
Int. J. Mol. Sci. 2023, 24(8), 7248; https://doi.org/10.3390/ijms24087248 - 14 Apr 2023
Cited by 1 | Viewed by 1534
Abstract
Studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in regulating virus infection, host immune response, and other biological processes. Although some lncRNAs have been reported to be involved in antiviral immunity, many lncRNAs have unknown functions in interactions between the [...] Read more.
Studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in regulating virus infection, host immune response, and other biological processes. Although some lncRNAs have been reported to be involved in antiviral immunity, many lncRNAs have unknown functions in interactions between the host and various viruses, especially influenza A virus (IAV). Herein, we demonstrate that the expression of lncRNA LINC02574 can be induced by IAV infection. Treatment with viral genomic RNA, poly (I:C), or interferons (IFNs) significantly stimulated LINC02574 expression, while RIG-I knockdown and IFNAR1 knockout significantly decreased LINC02574 expression after viral infection or IFN treatment. In addition, inhibition of LINC02574 expression in A549 cells enhanced IAV replication, while overexpression of LINC02574 inhibited viral production. Interestingly, knockdown of LINC02574 attenuated the expression of type I and type III IFNs and multiple ISGs, as well as the activation of STAT1 triggered by IAV infection. Moreover, LINC02574 deficiency impaired the expression of RIG-I, TLR3, and MDA5, and decreased the phosphorylation level of IRF3. In conclusion, the RIG-I-dependent interferon signaling pathway can induce LINC02574 expression. Moreover, the data reveal that LINC02574 inhibits IAV replication by positively regulating the innate immune response. Full article
Show Figures

Figure 1

20 pages, 901 KiB  
Review
Intestinal Microbiota and miRNA in IBD: A Narrative Review about Discoveries and Perspectives for the Future
by Ellen Cristina Souza de Oliveira, Ana Elisa Valencise Quaglio, Daniéla Oliveira Magro, Luiz Claudio Di Stasi and Ligia Yukie Sassaki
Int. J. Mol. Sci. 2023, 24(8), 7176; https://doi.org/10.3390/ijms24087176 - 13 Apr 2023
Cited by 5 | Viewed by 2110
Abstract
Inflammatory bowel disease (IBD) includes Crohn’s disease (CD) and ulcerative colitis (UC) and comprises a chronic gastrointestinal tract disorder characterized by hyperactive and dysregulated immune responses to environmental factors, including gut microbiota and dietary components. An imbalance of the intestinal microbiota may contribute [...] Read more.
Inflammatory bowel disease (IBD) includes Crohn’s disease (CD) and ulcerative colitis (UC) and comprises a chronic gastrointestinal tract disorder characterized by hyperactive and dysregulated immune responses to environmental factors, including gut microbiota and dietary components. An imbalance of the intestinal microbiota may contribute to the development and/or worsening of the inflammatory process. MicroRNAs (miRNAs) have been associated with various physiological processes, such as cell development and proliferation, apoptosis, and cancer. In addition, they play an important role in inflammatory processes, acting in the regulation of pro- and anti-inflammatory pathways. Differences in the profiles of miRNAs may represent a useful tool in the diagnosis of UC and CD and as a prognostic marker in both diseases. The relationship between miRNAs and the intestinal microbiota is not completely elucidated, but recently this topic has gained prominence and has become the target of several studies that demonstrate the role of miRNAs in the modulation of the intestinal microbiota and induction of dysbiosis; the microbiota, in turn, can regulate the expression of miRNAs and, consequently, alter the intestinal homeostasis. Therefore, this review aims to describe the interaction between the intestinal microbiota and miRNAs in IBD, recent discoveries, and perspectives for the future. Full article
Show Figures

Figure 1

16 pages, 5573 KiB  
Article
G-Quadruplexes Regulate miRNA Biogenesis in Live Zebrafish Embryos
by Tomás J. Steeman, Andrea M. J. Weiner, Aldana P. David, Andrés Binolfi, Nora B. Calcaterra and Pablo Armas
Int. J. Mol. Sci. 2023, 24(5), 4828; https://doi.org/10.3390/ijms24054828 - 02 Mar 2023
Cited by 1 | Viewed by 1581
Abstract
RNA guanine quadruplexes (G4s) regulate RNA functions, metabolism, and processing. G4s formed within precursors of microRNAs (pre-miRNAs) may impair pre-miRNAs maturation by Dicer, thus repressing mature miRNA biogenesis. As miRNAs are essential for proper embryonic development, we studied the role of G4s on [...] Read more.
RNA guanine quadruplexes (G4s) regulate RNA functions, metabolism, and processing. G4s formed within precursors of microRNAs (pre-miRNAs) may impair pre-miRNAs maturation by Dicer, thus repressing mature miRNA biogenesis. As miRNAs are essential for proper embryonic development, we studied the role of G4s on miRNA biogenesis in vivo during zebrafish embryogenesis. We performed a computational analysis on zebrafish pre-miRNAs to find putative G4 forming sequences (PQSs). The precursor of the miRNA 150 (pre-miR-150) was found to contain an evolutionarily conserved PQS formed by three G-tetrads and able to fold in vitro as G4. MiR-150 controls the expression of myb, which shows a well-defined knock-down phenotype in zebrafish developing embryos. We microinjected zebrafish embryos with in vitro transcribed pre-miR-150 synthesized using either GTP (G-pre-miR-150) or 7-Deaza-GTP, a GTP analogue unable to form G4s (7DG-pre-miR-150). Compared to embryos injected with G-pre-miR-150, embryos injected with 7DG-pre-miR-150 showed higher levels of miRNA 150 (miR-150) and lower levels of myb mRNA and stronger phenotypes associated with myb knock-down. The incubation of pre-miR-150 prior to the injection with the G4 stabilizing ligand pyridostatin (PDS) reverted gene expression variations and rescued the phenotypes related to myb knock-down. Overall, results suggest that the G4 formed in pre-miR-150 functions in vivo as a conserved regulatory structure competing with the stem-loop structure necessary for miRNA biogenesis. Full article
Show Figures

Figure 1

15 pages, 2978 KiB  
Article
Circulating miR-122-5p, miR-92a-3p, and miR-18a-5p as Potential Biomarkers in Human Liver Transplantation Follow-Up
by Cristina Morsiani, Salvatore Collura, Federica Sevini, Erika Ciurca, Valentina Rosa Bertuzzo, Claudio Franceschi, Gian Luca Grazi, Matteo Cescon and Miriam Capri
Int. J. Mol. Sci. 2023, 24(4), 3457; https://doi.org/10.3390/ijms24043457 - 09 Feb 2023
Cited by 2 | Viewed by 1391
Abstract
The requirement of blood-circulating sensitive biomarkers for monitoring liver transplant (LT) is currently a necessary step aiming at the reduction of standard invasive protocols, such as liver biopsy. In this respect, the main objective of this study is to assess circulating microRNA (c-miR) [...] Read more.
The requirement of blood-circulating sensitive biomarkers for monitoring liver transplant (LT) is currently a necessary step aiming at the reduction of standard invasive protocols, such as liver biopsy. In this respect, the main objective of this study is to assess circulating microRNA (c-miR) changes in recipients’ blood before and after LT and to correlate their blood levels with gold standard biomarkers and with outcomes such as rejection or complications after graft. An miR profile was initially performed; then, the most deregulated miRs were validated by RT-qPCR in 14 recipients pre- and post-LT and compared to a control group of 24 nontransplanted healthy subjects. MiR-122-5p, miR-92a-3p, miR-18a-5p, and miR-30c-5p, identified in the validation phase, were also analyzed considering an additional 19 serum samples collected from LT recipients and focusing on different follow-up (FU) times. The results showed significant, FU-related changes in c-miRs. In particular, miR-122-5p, miR-92a-3p, and miR-18a-5p revealed the same trend after transplantation and an increase in their level was found in patients with complications, independently from FU times. Conversely, the variations in the standard haemato-biochemical parameters for liver function assessment were not significant in the same FU period, confirming the importance of c-miRs as potential noninvasive biomarkers for monitoring patients’ outcomes. Full article
Show Figures

Figure 1

2022

Jump to: 2023, 2021, 2020, 2019, 2018, 2017, 2016, 2015, 2014

30 pages, 1617 KiB  
Review
Long Noncoding RNAs in the Pathogenesis of Insulin Resistance
by Weili Yang, Yixiang Lyu, Rui Xiang and Jichun Yang
Int. J. Mol. Sci. 2022, 23(24), 16054; https://doi.org/10.3390/ijms232416054 - 16 Dec 2022
Cited by 10 | Viewed by 2284
Abstract
Insulin resistance (IR), designated as the blunted response of insulin target tissues to physiological level of insulin, plays crucial roles in the development and progression of diabetes, nonalcoholic fatty liver disease (NAFLD) and other diseases. So far, the distinct mechanism(s) of IR still [...] Read more.
Insulin resistance (IR), designated as the blunted response of insulin target tissues to physiological level of insulin, plays crucial roles in the development and progression of diabetes, nonalcoholic fatty liver disease (NAFLD) and other diseases. So far, the distinct mechanism(s) of IR still needs further exploration. Long non-coding RNA (lncRNA) is a class of non-protein coding RNA molecules with a length greater than 200 nucleotides. LncRNAs are widely involved in many biological processes including cell differentiation, proliferation, apoptosis and metabolism. More recently, there has been increasing evidence that lncRNAs participated in the pathogenesis of IR, and the dysregulated lncRNA profile played important roles in the pathogenesis of metabolic diseases including obesity, diabetes and NAFLD. For example, the lncRNAs MEG3, H19, MALAT1, GAS5, lncSHGL and several other lncRNAs have been shown to regulate insulin signaling and glucose/lipid metabolism in various tissues. In this review, we briefly introduced the general features of lncRNA and the methods for lncRNA research, and then summarized and discussed the recent advances on the roles and mechanisms of lncRNAs in IR, particularly focused on liver, skeletal muscle and adipose tissues. Full article
Show Figures

Figure 1

20 pages, 3081 KiB  
Review
What Do We Know about Barley miRNAs?
by Adriana Volná, Martin Bartas, Petr Pečinka, Vladimír Špunda and Jiří Červeň
Int. J. Mol. Sci. 2022, 23(23), 14755; https://doi.org/10.3390/ijms232314755 - 25 Nov 2022
Cited by 2 | Viewed by 4049
Abstract
Plant miRNAs are powerful regulators of gene expression at the post-transcriptional level, which was repeatedly proved in several model plant species. miRNAs are considered to be key regulators of many developmental, homeostatic, and immune processes in plants. However, our understanding of plant miRNAs [...] Read more.
Plant miRNAs are powerful regulators of gene expression at the post-transcriptional level, which was repeatedly proved in several model plant species. miRNAs are considered to be key regulators of many developmental, homeostatic, and immune processes in plants. However, our understanding of plant miRNAs is still limited, despite the fact that an increasing number of studies have appeared. This systematic review aims to summarize our current knowledge about miRNAs in spring barley (Hordeum vulgare), which is an important agronomical crop worldwide and serves as a common monocot model for studying abiotic stress responses as well. This can help us to understand the connection between plant miRNAs and (not only) abiotic stresses in general. In the end, some future perspectives and open questions are summarized. Full article
Show Figures

Figure 1

19 pages, 1594 KiB  
Review
Enhancer RNA (eRNA) in Human Diseases
by Yunzhe Wang, Chenyang Zhang, Yuxiang Wang, Xiuping Liu and Zhao Zhang
Int. J. Mol. Sci. 2022, 23(19), 11582; https://doi.org/10.3390/ijms231911582 - 30 Sep 2022
Cited by 1 | Viewed by 2792
Abstract
Enhancer RNAs (eRNAs), a class of non-coding RNAs (ncRNAs) transcribed from enhancer regions, serve as a type of critical regulatory element in gene expression. There is increasing evidence demonstrating that the aberrant expression of eRNAs can be broadly detected in various human diseases. [...] Read more.
Enhancer RNAs (eRNAs), a class of non-coding RNAs (ncRNAs) transcribed from enhancer regions, serve as a type of critical regulatory element in gene expression. There is increasing evidence demonstrating that the aberrant expression of eRNAs can be broadly detected in various human diseases. Some studies also revealed the potential clinical utility of eRNAs in these diseases. In this review, we summarized the recent studies regarding the pathological mechanisms of eRNAs as well as their potential utility across human diseases, including cancers, neurodegenerative disorders, cardiovascular diseases and metabolic diseases. It could help us to understand how eRNAs are engaged in the processes of diseases and to obtain better insight of eRNAs in diagnosis, prognosis or therapy. The studies we reviewed here indicate the enormous therapeutic potency of eRNAs across human diseases. Full article
Show Figures

Figure 1

20 pages, 1302 KiB  
Review
A Survey on Computational Methods for Investigation on ncRNA-Disease Association through the Mode of Action Perspective
by Dongmin Bang, Jeonghyeon Gu, Joonhyeong Park, Dabin Jeong, Bonil Koo, Jungseob Yi, Jihye Shin, Inuk Jung, Sun Kim and Sunho Lee
Int. J. Mol. Sci. 2022, 23(19), 11498; https://doi.org/10.3390/ijms231911498 - 29 Sep 2022
Cited by 3 | Viewed by 2038
Abstract
Molecular and sequencing technologies have been successfully used in decoding biological mechanisms of various diseases. As revealed by many novel discoveries, the role of non-coding RNAs (ncRNAs) in understanding disease mechanisms is becoming increasingly important. Since ncRNAs primarily act as regulators of transcription, [...] Read more.
Molecular and sequencing technologies have been successfully used in decoding biological mechanisms of various diseases. As revealed by many novel discoveries, the role of non-coding RNAs (ncRNAs) in understanding disease mechanisms is becoming increasingly important. Since ncRNAs primarily act as regulators of transcription, associating ncRNAs with diseases involves multiple inference steps. Leveraging the fast-accumulating high-throughput screening results, a number of computational models predicting ncRNA-disease associations have been developed. These tools suggest novel disease-related biomarkers or therapeutic targetable ncRNAs, contributing to the realization of precision medicine. In this survey, we first introduce the biological roles of different ncRNAs and summarize the databases containing ncRNA-disease associations. Then, we suggest a new trend in recent computational prediction of ncRNA-disease association, which is the mode of action (MoA) network perspective. This perspective includes integrating ncRNAs with mRNA, pathway and phenotype information. In the next section, we describe computational methodologies widely used in this research domain. Existing computational studies are then summarized in terms of their coverage of the MoA network. Lastly, we discuss the potential applications and future roles of the MoA network in terms of integrating biological mechanisms for ncRNA-disease associations. Full article
Show Figures

Figure 1

12 pages, 1036 KiB  
Review
miR-140-5p and miR-140-3p: Key Actors in Aging-Related Diseases?
by Léa Toury, Diane Frankel, Coraline Airault, Frédérique Magdinier, Patrice Roll and Elise Kaspi
Int. J. Mol. Sci. 2022, 23(19), 11439; https://doi.org/10.3390/ijms231911439 - 28 Sep 2022
Cited by 6 | Viewed by 1691
Abstract
microRNAs (miRNAs) are small single strand non-coding RNAs and powerful gene expression regulators. They mainly bind to the 3′UTR sequence of targeted mRNA, leading to their degradation or translation inhibition. miR-140 gene encodes the pre-miR-140 that generates the two mature miRNAs miR-140-5p and [...] Read more.
microRNAs (miRNAs) are small single strand non-coding RNAs and powerful gene expression regulators. They mainly bind to the 3′UTR sequence of targeted mRNA, leading to their degradation or translation inhibition. miR-140 gene encodes the pre-miR-140 that generates the two mature miRNAs miR-140-5p and miR-140-3p. miR-140-5p/-3p have been associated with the development and progression of cancers, but also non-neoplastic diseases. In aging-related diseases, miR-140-5p and miR-140-3p expressions are modulated. The seric levels of these two miRNAs are used as circulating biomarkers and may represent predictive tools. They are also considered key actors in the pathophysiology of aging-related diseases. miR-140-5p/-3p repress targets regulating cell proliferation, apoptosis, senescence, and inflammation. This work focuses on the roles of miR-140-3p and miR-140-5p in aging-related diseases, details their regulation (i.e., by long non-coding RNA), and reviews the molecular targets of theses miRNAs involved in aging pathophysiology. Full article
Show Figures

Figure 1

14 pages, 2212 KiB  
Article
A Functional Network Driven by MicroRNA-125a Regulates Monocyte Trafficking in Acute Inflammation
by Stephanie Tomasi, Lei Li, Ludwig Christian Hinske, Roland Tomasi, Martina Amini, Gabriele Strauß, Martin Bernhard Müller, Simon Hirschberger, Sven Peterss, David Effinger, Kristin Pogoda, Simone Kreth and Max Hübner
Int. J. Mol. Sci. 2022, 23(18), 10684; https://doi.org/10.3390/ijms231810684 - 14 Sep 2022
Cited by 1 | Viewed by 1492
Abstract
During the onset of acute inflammation, rapid trafficking of leukocytes is essential to mount appropriate immune responses towards an inflammatory insult. Monocytes are especially indispensable for counteracting the inflammatory stimulus, neutralising the noxa and reconstituting tissue homeostasis. Thus, monocyte trafficking to the inflammatory [...] Read more.
During the onset of acute inflammation, rapid trafficking of leukocytes is essential to mount appropriate immune responses towards an inflammatory insult. Monocytes are especially indispensable for counteracting the inflammatory stimulus, neutralising the noxa and reconstituting tissue homeostasis. Thus, monocyte trafficking to the inflammatory sites needs to be precisely orchestrated. In this study, we identify a regulatory network driven by miR-125a that affects monocyte adhesion and chemotaxis by the direct targeting of two adhesion molecules, i.e., junction adhesion molecule A (JAM-A), junction adhesion molecule-like (JAM-L) and the chemotaxis-mediating chemokine receptor CCR2. By investigating monocytes isolated from patients undergoing cardiac surgery, we found that acute yet sterile inflammation reduces miR-125a levels, concomitantly enhancing the expression of JAM-A, JAM-L and CCR2. In contrast, TLR-4-specific stimulation with the pathogen-associated molecular pattern (PAMP) LPS, usually present within the perivascular inflamed area, resulted in dramatically induced levels of miR-125a with concomitant repression of JAM-A, JAM-L and CCR2 as early as 3.5 h. Our study identifies miR-125a as an important regulator of monocyte trafficking and shows that the phenotype of human monocytes is strongly influenced by this miRNA, depending on the type of inflammatory stimulus. Full article
Show Figures

Figure 1

21 pages, 3546 KiB  
Article
Upregulation of the Long Noncoding RNA CASC10 Promotes Cisplatin Resistance in High-Grade Serous Ovarian Cancer
by Ricardo Noriega-Rivera, Mariela Rivera-Serrano, Robert J. Rabelo-Fernandez, Josué Pérez-Santiago, Fatima Valiyeva and Pablo E. Vivas-Mejía
Int. J. Mol. Sci. 2022, 23(14), 7737; https://doi.org/10.3390/ijms23147737 - 13 Jul 2022
Cited by 5 | Viewed by 2268
Abstract
Despite initial responses to first-line treatment with platinum and taxane-based combination chemotherapy, most high-grade serous ovarian carcinoma (HGSOC) patients will relapse and eventually develop a cisplatin-resistant fatal disease. Due to the lethality of this disease, there is an urgent need to develop improved [...] Read more.
Despite initial responses to first-line treatment with platinum and taxane-based combination chemotherapy, most high-grade serous ovarian carcinoma (HGSOC) patients will relapse and eventually develop a cisplatin-resistant fatal disease. Due to the lethality of this disease, there is an urgent need to develop improved targeted therapies against HGSOC. Herein, we identified CASC10, a long noncoding RNA upregulated in cisplatin-resistant ovarian cancer cells and ovarian cancer patients. We performed RNA sequencing (RNA-seq) in total RNA isolated from the HGSOC cell lines OVCAR3 and OV-90 and their cisplatin-resistant counterparts. Thousands of RNA transcripts were differentially abundant in cisplatin-sensitive vs. cisplatin-resistant HGSOC cells. Further data filtering unveiled CASC10 as one of the top RNA transcripts significantly increased in cisplatin-resistant compared with cisplatin-sensitive cells. Thus, we focused our studies on CASC10, a gene not previously studied in ovarian cancer. SiRNA-mediated CASC10 knockdown significantly reduced cell proliferation and invasion; and sensitized cells to cisplatin treatment. SiRNA-mediated CASC10 knockdown also induced apoptosis, cell cycle arrest, and altered the expression of several CASC10 downstream effectors. Multiple injections of liposomal CASC10-siRNA reduced tumor growth and metastasis in an ovarian cancer mouse model. Our results demonstrated that CASC10 levels mediate the susceptibility of HGSOC cells to cisplatin treatment. Thus, combining siRNA-mediated CASC10 knockdown with cisplatin may represent a plausible therapeutic strategy against HGSOC. Full article
Show Figures

Figure 1

17 pages, 3890 KiB  
Article
Characterization of Adrenal miRNA-Based Dysregulations in Cushing’s Syndrome
by Sharmilee Vetrivel, Ru Zhang, Mareen Engel, Andrea Oßwald, Deepika Watts, Alon Chen, Ben Wielockx, Silviu Sbiera, Martin Reincke and Anna Riester
Int. J. Mol. Sci. 2022, 23(14), 7676; https://doi.org/10.3390/ijms23147676 - 12 Jul 2022
Cited by 6 | Viewed by 2117
Abstract
MiRNAs are important epigenetic players with tissue- and disease-specific effects. In this study, our aim was to investigate the putative differential expression of miRNAs in adrenal tissues from different forms of Cushing’s syndrome (CS). For this, miRNA-based next-generation sequencing was performed in adrenal [...] Read more.
MiRNAs are important epigenetic players with tissue- and disease-specific effects. In this study, our aim was to investigate the putative differential expression of miRNAs in adrenal tissues from different forms of Cushing’s syndrome (CS). For this, miRNA-based next-generation sequencing was performed in adrenal tissues taken from patients with ACTH-independent cortisol-producing adrenocortical adenomas (CPA), from patients with ACTH-dependent pituitary Cushing’s disease (CD) after bilateral adrenalectomy, and from control subjects. A confirmatory QPCR was also performed in adrenals from patients with other CS subtypes, such as primary bilateral macronodular hyperplasia and ectopic CS. Sequencing revealed significant differences in the miRNA profiles of CD and CPA. QPCR revealed the upregulated expression of miR-1247-5p in CPA and PBMAH (log2 fold change > 2.5, p < 0.05). MiR-379-5p was found to be upregulated in PBMAH and CD (log2 fold change > 1.8, p < 0.05). Analyses of miR-1247-5p and miR-379-5p expression in the adrenals of mice which had been exposed to short-term ACTH stimulation showed no influence on the adrenal miRNA expression profiles. For miRNA-specific target prediction, RNA-seq data from the adrenals of CPA, PBMAH, and control samples were analyzed with different bioinformatic platforms. The analyses revealed that both miR-1247-5p and miR-379-5p target specific genes in the WNT signaling pathway. In conclusion, this study identified distinct adrenal miRNAs as being associated with CS subtypes. Full article
Show Figures

Figure 1

23 pages, 2342 KiB  
Review
LncRNA-Mediated Adipogenesis in Different Adipocytes
by Peiwen Zhang, Shuang Wu, Yuxu He, Xinrong Li, Yan Zhu, Xutao Lin, Lei Chen, Ye Zhao, Lili Niu, Shunhua Zhang, Xuewei Li, Li Zhu and Linyuan Shen
Int. J. Mol. Sci. 2022, 23(13), 7488; https://doi.org/10.3390/ijms23137488 - 05 Jul 2022
Cited by 16 | Viewed by 4353
Abstract
Long-chain noncoding RNAs (lncRNAs) are RNAs that do not code for proteins, widely present in eukaryotes. They regulate gene expression at multiple levels through different mechanisms at epigenetic, transcription, translation, and the maturation of mRNA transcripts or regulation of the chromatin structure, and [...] Read more.
Long-chain noncoding RNAs (lncRNAs) are RNAs that do not code for proteins, widely present in eukaryotes. They regulate gene expression at multiple levels through different mechanisms at epigenetic, transcription, translation, and the maturation of mRNA transcripts or regulation of the chromatin structure, and compete with microRNAs for binding to endogenous RNA. Adipose tissue is a large and endocrine-rich functional tissue in mammals. Excessive accumulation of white adipose tissue in mammals can cause metabolic diseases. However, unlike white fat, brown and beige fats release energy as heat. In recent years, many lncRNAs associated with adipogenesis have been reported. The molecular mechanisms of how lncRNAs regulate adipogenesis are continually investigated. In this review, we discuss the classification of lncRNAs according to their transcriptional location. lncRNAs that participate in the adipogenesis of white or brown fats are also discussed. The function of lncRNAs as decoy molecules and RNA double-stranded complexes, among other functions, is also discussed. Full article
Show Figures

Figure 1

13 pages, 4263 KiB  
Article
Comprehensive Identification of Human Cell Type Chromatin Activity-Specific and Cell Type Expression-Specific MicroRNAs
by Yu Han and Yuan Zhou
Int. J. Mol. Sci. 2022, 23(13), 7324; https://doi.org/10.3390/ijms23137324 - 30 Jun 2022
Viewed by 1289
Abstract
MicroRNAs (miRNAs) regulate multiple transcripts and thus shape the expression landscape of a cell. Information about miRNA expression and distribution across cell types is crucial for the understanding of miRNAs’ functions and their translational applications as biomarkers or therapeutic targets. In this study, [...] Read more.
MicroRNAs (miRNAs) regulate multiple transcripts and thus shape the expression landscape of a cell. Information about miRNA expression and distribution across cell types is crucial for the understanding of miRNAs’ functions and their translational applications as biomarkers or therapeutic targets. In this study, we identify cell-type-specific miRNAs by combining multiple correspondence analysis and Gini coefficients to dissect miRNAs’ expression profiles and chromatin activity score profiles, which results in collections of chromatin activity-specific miRNAs in 91 cell types and expression-specific miRNAs in 124 cell types. Moreover, we find that cell-type-specific miRNAs are closely associated with disease miRNAs, such as T-cell-specific miRNAs, which are closely associated with cancer prognosis. Finally, we constructed mirCellType, an online tool based on cell-type-specific miRNA signatures, to dissect the cell type composition of complex samples with miRNA expression profiles. Full article
Show Figures

Figure 1

18 pages, 2969 KiB  
Review
Critical Roles of Circular RNA in Tumor Metastasis via Acting as a Sponge of miRNA/isomiR
by Li Guo, Lin Jia, Lulu Luo, Xinru Xu, Yangyang Xiang, Yujie Ren, Dekang Ren, Lulu Shen and Tingming Liang
Int. J. Mol. Sci. 2022, 23(13), 7024; https://doi.org/10.3390/ijms23137024 - 24 Jun 2022
Cited by 16 | Viewed by 2595
Abstract
Circular RNAs (circRNAs), a class of new endogenous non-coding RNAs (ncRNAs), are closely related to the carcinogenic process and play a critical role in tumor metastasis. CircRNAs can lay the foundation for tumor metastasis via promoting tumor angiogenesis, make tumor cells gain the [...] Read more.
Circular RNAs (circRNAs), a class of new endogenous non-coding RNAs (ncRNAs), are closely related to the carcinogenic process and play a critical role in tumor metastasis. CircRNAs can lay the foundation for tumor metastasis via promoting tumor angiogenesis, make tumor cells gain the ability of migration and invasion by regulating epithelial-mesenchymal transition (EMT), interact with immune cells, cytokines, chemokines, and other non-cellular components in the tumor microenvironment, damage the normal immune function or escape the immunosuppressive network, and further promote cell survival and metastasis. Herein, based on the characteristics and biological functions of circRNA, we elaborated on the effect of circRNA via circRNA-associated competing endogenous RNA (ceRNA) network by acting as miRNA/isomiR sponges on tumor angiogenesis, cancer cell migration and invasion, and interaction with the tumor microenvironment (TME), then explored the potential interactions across different RNAs, and finally discussed the potential clinical value and application as a promising biomarker. These results provide a theoretical basis for the further application of metastasis-related circRNAs in cancer treatment. In summary, we briefly summarize the diverse roles of a circRNA-associated ceRNA network in cancer metastasis and the potential clinical application, especially the interaction of circRNA and miRNA/isomiR, which may complicate the RNA regulatory network and which will contribute to a novel insight into circRNA in the future. Full article
Show Figures

Figure 1

32 pages, 28001 KiB  
Article
Single-Cell Atlas of the Drosophila Leg Disc Identifies a Long Non-Coding RNA in Late Development
by Joyce Tse, Tsz Ho Li, Jizhou Zhang, Alan Chun Kit Lee, Ivy Lee, Zhe Qu, Xiao Lin, Jerome Hui and Ting-Fung Chan
Int. J. Mol. Sci. 2022, 23(12), 6796; https://doi.org/10.3390/ijms23126796 - 18 Jun 2022
Cited by 3 | Viewed by 2623
Abstract
The Drosophila imaginal disc has been an excellent model for the study of developmental gene regulation. In particular, long non-coding RNAs (lncRNAs) have gained widespread attention in recent years due to their important role in gene regulation. Their specific spatiotemporal expressions further support [...] Read more.
The Drosophila imaginal disc has been an excellent model for the study of developmental gene regulation. In particular, long non-coding RNAs (lncRNAs) have gained widespread attention in recent years due to their important role in gene regulation. Their specific spatiotemporal expressions further support their role in developmental processes and diseases. In this study, we explored the role of a novel lncRNA in Drosophila leg development by dissecting and dissociating w1118 third-instar larval third leg (L3) discs into single cells and single nuclei, and performing single-cell RNA-sequencing (scRNA-seq) and single-cell assays for transposase-accessible chromatin (scATAC-seq). Single-cell transcriptomics analysis of the L3 discs across three developmental timepoints revealed different cell types and identified lncRNA:CR33938 as a distal specific gene with high expression in late development. This was further validated by fluorescence in-situ hybridization (FISH). The scATAC-seq results reproduced the single-cell transcriptomics landscape and elucidated the distal cell functions at different timepoints. Furthermore, overexpression of lncRNA:CR33938 in the S2 cell line increased the expression of leg development genes, further elucidating its potential role in development. Full article
Show Figures

Figure 1

14 pages, 2293 KiB  
Article
Secreted miR-153 Controls Proliferation and Invasion of Higher Gleason Score Prostate Cancer
by Gloria Bertoli, Antonella Panio, Claudia Cava, Francesca Gallivanone, Martina Alini, Giulia Strano, Federico Molfino, Loredana Brioschi, Paola Viani and Danilo Porro
Int. J. Mol. Sci. 2022, 23(11), 6339; https://doi.org/10.3390/ijms23116339 - 06 Jun 2022
Cited by 8 | Viewed by 2075
Abstract
Prostate cancer (PC) is a male common neoplasm and is the second leading cause of cancer death in American men. PC is traditionally diagnosed by the evaluation of prostate secreted antigen (PSA) in the blood. Due to the high levels of false positives, [...] Read more.
Prostate cancer (PC) is a male common neoplasm and is the second leading cause of cancer death in American men. PC is traditionally diagnosed by the evaluation of prostate secreted antigen (PSA) in the blood. Due to the high levels of false positives, digital rectal examination and transrectal ultrasound guided biopsy are necessary in uncertain cases with elevated PSA levels. Nevertheless, the high mortality rate suggests that new PC biomarkers are urgently needed to help clinical diagnosis. In a previous study, we have identified a network of genes, altered in high Gleason Score (GS) PC (GS ≥ 7), being regulated by miR-153. Until now, no publication has explained the mechanism of action of miR-153 in PC. By in vitro studies, we found that the overexpression of miR-153 in high GS cell lines is required to control cell proliferation, migration and invasion rates, targeting Kruppel-like factor 5 (KLF5). Moreover, miR-153 could be secreted by exosomes and microvesicles in the microenvironment and, once entered into the surrounding tissue, could influence cellular growth. Being upregulated in high GS human PC, miR-153 could be proposed as a circulating biomarker for PC diagnosis. Full article
Show Figures

Figure 1

11 pages, 900 KiB  
Review
Emerging Functions of lncRNA Loci beyond the Transcript Itself
by Hober Nelson Núñez-Martínez and Félix Recillas-Targa
Int. J. Mol. Sci. 2022, 23(11), 6258; https://doi.org/10.3390/ijms23116258 - 02 Jun 2022
Cited by 16 | Viewed by 3255
Abstract
Thousands of long noncoding RNAs (lncRNAs) are actively transcribed in mammalian genomes. This class of RNAs has important regulatory functions in a broad range of cellular processes and diseases. Numerous lncRNAs have been demonstrated to mediate gene regulation through RNA-based mechanisms. Simultaneously, non-functional [...] Read more.
Thousands of long noncoding RNAs (lncRNAs) are actively transcribed in mammalian genomes. This class of RNAs has important regulatory functions in a broad range of cellular processes and diseases. Numerous lncRNAs have been demonstrated to mediate gene regulation through RNA-based mechanisms. Simultaneously, non-functional lncRNA transcripts derived from the activity of lncRNA loci have been identified, which underpin the notion that a considerable fraction of lncRNA loci exert regulatory functions through mechanisms associated with the production or the activity of lncRNA loci beyond the synthesized transcripts. We particularly distinguish two main RNA-independent components associated with regulatory effects; the act of transcription and the activity of DNA regulatory elements. We describe the experimental approaches to distinguish and understand the functional mechanisms derived from lncRNA loci. These scenarios reveal emerging mechanisms important to understanding the lncRNA implications in genome biology. Full article
Show Figures

Figure 1

15 pages, 3066 KiB  
Article
Alteration of Gene and miRNA Expression in Cervical Intraepithelial Neoplasia and Cervical Cancer
by Marina Dudea-Simon, Dan Mihu, Laura Ancuta Pop, Razvan Ciortea, Andrei Mihai Malutan, Doru Diculescu, Cristina Alexandra Ciocan, Roxana Maria Cojocneanu, Vasile Simon, Carmen Bucuri, Radu Mocan-Hognogi, Cornelia Braicu and Ioana Berindan-Neagoe
Int. J. Mol. Sci. 2022, 23(11), 6054; https://doi.org/10.3390/ijms23116054 - 27 May 2022
Cited by 4 | Viewed by 1933
Abstract
Background: Cervical cancer is one of the most common malignancies in women in terms of prevalence and mortality. Cervical cancer has some particularities that distinguish it from any other oncologic pathology: first, it is completely preventable by prompt detection of its precursor, [...] Read more.
Background: Cervical cancer is one of the most common malignancies in women in terms of prevalence and mortality. Cervical cancer has some particularities that distinguish it from any other oncologic pathology: first, it is completely preventable by prompt detection of its precursor, cervical intraepithelial neoplasia (CIN); second, the Human Papillomavirus (HPV) infection is a known etiological agent; third, the mean age at diagnosis is much lower than in other oncologic conditions, as a consequence of the sexually-transmitted HPV. Methods: We evaluated the expression level of several long noncoding RNAs and a microRNA in samples from 30 patients with CIN, 9 with cervical cancer and 38 normal samples using qRT-PCR technology. Results: We observed higher expression levels for MEG3, DAPK1, MLH1 and MALAT1 in CIN samples than in normal samples, whereas TIMP3 and SOX1 had lower expression levels. For cancer samples, DAPK1, MLH1 and MALAT1 had higher expression, and MEG3, TIMP3 and SOX1 had lower expression when compared to normal samples. In the case of CIN versus cancer samples, only MEG3 gene showed a statistically significant difference. The expression of miR-205-5p was lower in both CIN and cancer samples compared to normal samples. Conclusion: Decreased MEG3 expression could be considered an alarm signal in the transition from a premalignant cervical lesion to invasive cancer, while altered expression levels of TIMP3, SOX1, MLH1, MALAT1 and miR-205-5p could serve as early biomarkers in the diagnosis of premalignant cervical lesions. Future studies, including a larger number of patients with CIN, will be of particular importance in validating these observations. Full article
Show Figures

Figure 1

32 pages, 3437 KiB  
Review
Expression and Biological Functions of miRNAs in Chronic Pain: A Review on Human Studies
by Saverio Sabina, Alessandra Panico, Pierpaolo Mincarone, Carlo Giacomo Leo, Sergio Garbarino, Tiziana Grassi, Francesco Bagordo, Antonella De Donno, Egeria Scoditti and Maria Rosaria Tumolo
Int. J. Mol. Sci. 2022, 23(11), 6016; https://doi.org/10.3390/ijms23116016 - 27 May 2022
Cited by 8 | Viewed by 2239
Abstract
Chronic pain is a major public health problem and an economic burden worldwide. However, its underlying pathological mechanisms remain unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in physiological and pathological processes. [...] Read more.
Chronic pain is a major public health problem and an economic burden worldwide. However, its underlying pathological mechanisms remain unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in physiological and pathological processes. This review aims to synthesize the human studies examining miRNA expression in the pathogenesis of chronic primary pain and chronic secondary pain. Additionally, to understand the potential pathophysiological impact of miRNAs in these conditions, an in silico analysis was performed to reveal the target genes and pathways involved in primary and secondary pain and their differential regulation in the different types of chronic pain. The findings, methodological issues and challenges of miRNA research in the pathophysiology of chronic pain are discussed. The available evidence suggests the potential role of miRNA in disease pathogenesis and possibly the pain process, eventually enabling this role to be exploited for pain monitoring and management. Full article
Show Figures

Figure 1

35 pages, 2471 KiB  
Review
Histone Modifications and Non-Coding RNAs: Mutual Epigenetic Regulation and Role in Pathogenesis
by Irina V. Bure, Marina V. Nemtsova and Ekaterina B. Kuznetsova
Int. J. Mol. Sci. 2022, 23(10), 5801; https://doi.org/10.3390/ijms23105801 - 22 May 2022
Cited by 27 | Viewed by 5039
Abstract
In the last few years, more and more scientists have suggested and confirmed that epigenetic regulators are tightly connected and form a comprehensive network of regulatory pathways and feedback loops. This is particularly interesting for a better understanding of processes that occur in [...] Read more.
In the last few years, more and more scientists have suggested and confirmed that epigenetic regulators are tightly connected and form a comprehensive network of regulatory pathways and feedback loops. This is particularly interesting for a better understanding of processes that occur in the development and progression of various diseases. Appearing on the preclinical stages of diseases, epigenetic aberrations may be prominent biomarkers. Being dynamic and reversible, epigenetic modifications could become targets for a novel option for therapy. Therefore, in this review, we are focusing on histone modifications and ncRNAs, their mutual regulation, role in cellular processes and potential clinical application. Full article
Show Figures

Figure 1

14 pages, 1396 KiB  
Article
miR-22-3p and miR-30e-5p Are Associated with Prognosis in Cervical Squamous Cell Carcinoma
by Ah-Young Kwon, Ju-Yeon Jeong, Hyun Park, Sohyun Hwang, Gwangil Kim, Haeyoun Kang, Jin-Hyung Heo, Hye Jin Lee, Tae-Heon Kim and Hee Jung An
Int. J. Mol. Sci. 2022, 23(10), 5623; https://doi.org/10.3390/ijms23105623 - 17 May 2022
Cited by 6 | Viewed by 1649
Abstract
Alteration in expression of miRNAs can cause various malignant changes and the metastatic process. Our aim was to identify the miRNAs involved in cervical squamous cell carcinoma (SqCC) and metastasis, and to test their utility as indicators of metastasis and survival. Using microarray [...] Read more.
Alteration in expression of miRNAs can cause various malignant changes and the metastatic process. Our aim was to identify the miRNAs involved in cervical squamous cell carcinoma (SqCC) and metastasis, and to test their utility as indicators of metastasis and survival. Using microarray technology, we performed miRNA expression profiling on primary cervical SqCC tissue (n = 6) compared with normal control (NC) tissue and compared SqCC that had (SqC-M; n = 3) and had not (SqC-NM; n = 3) metastasized. Four miRNAs were selected for validation by qRT-PCR on 29 SqC-NM and 27 SqC-M samples, and nine metastatic lesions (ML-SqC), from a total of 56 patients. Correlation of miRNA expression and clinicopathological parameters was analyzed to evaluate the clinical impact of candidate miRNAs. We found 40 miRNAs differentially altered in cervical SqCC tissue: 21 miRNAs were upregulated and 19 were downregulated (≥2-fold, p < 0.05). Eight were differentially altered in SqC-M compared with SqC-NM samples: four were upregulated (miR-494, miR-92a-3p, miR-205-5p, and miR-221-3p), and four were downregulated (miR-574-3p, miR-4769-3p, miR-1281, and miR-1825) (≥1.5-fold, p < 0.05). MiR-22-3p might be a metastamiR, which was gradually further downregulated in SqC-NM > SqC-M > ML-SqC. Downregulation of miR-30e-5p significantly correlated with high stage, lymph node metastasis, and low survival rate, suggesting an independent poor prognostic factor. Full article
Show Figures

Figure 1

10 pages, 797 KiB  
Review
TRUE Gene Silencing
by Masayuki Nashimoto
Int. J. Mol. Sci. 2022, 23(10), 5387; https://doi.org/10.3390/ijms23105387 - 11 May 2022
Cited by 2 | Viewed by 1976
Abstract
TRUE gene silencing is an RNA-mediated gene expression control technology and is termed after tRNase ZL-utilizing efficacious gene silencing. In this review, I overview the potentiality of small guide RNA (sgRNA) for TRUE gene silencing as novel therapeutics. First, I describe [...] Read more.
TRUE gene silencing is an RNA-mediated gene expression control technology and is termed after tRNase ZL-utilizing efficacious gene silencing. In this review, I overview the potentiality of small guide RNA (sgRNA) for TRUE gene silencing as novel therapeutics. First, I describe the physiology of tRNase ZL and cellular small RNA, and then sgRNA and TRUE gene silencing. An endoribonuclease, tRNase ZL, which can efficiently remove a 3′ trailer from pre-tRNA, is thought to play the role in tRNA maturation in the nucleus and mitochondria. There exist various small RNAs including miRNA and fragments from tRNA and rRNA, which can function as sgRNA, in living cells, and human cells appear to be harnessing cytosolic tRNase ZL for gene regulation together with these small RNAs. By utilizing the property of tRNase ZL to recognize and cleave micro-pre-tRNA, a pre-tRNA-like or micro-pre-tRNA-like complex, as well as pre-tRNA, tRNase ZL can be made to cleave any target RNA at any desired site under the direction of an artificial sgRNA that binds a target RNA and forms the pre-tRNA-like or micro-pre-tRNA-like complex. This general RNA cleavage method underlies TRUE gene silencing. Various examples of the application of TRUE gene silencing are reviewed including the application to several human cancer cells in order to induce apoptosis. Lastly, I discuss the potentiality of sgRNA as novel therapeutics for multiple myeloma. Full article
Show Figures

Figure 1

15 pages, 796 KiB  
Review
MicroRNAs (miRNAs) in Cardiovascular Complications of Rheumatoid Arthritis (RA): What Is New?
by Daniela Maria Tanase, Evelina Maria Gosav, Daniela Petrov, Dan-Stefan Teodorescu, Oana Nicoleta Buliga-Finis, Anca Ouatu, Ionut Tudorancea, Elena Rezus and Ciprian Rezus
Int. J. Mol. Sci. 2022, 23(9), 5254; https://doi.org/10.3390/ijms23095254 - 08 May 2022
Cited by 6 | Viewed by 2522
Abstract
Rheumatoid Arthritis (RA) is among the most prevalent and impactful rheumatologic chronic autoimmune diseases (AIDs) worldwide. Within a framework that recognizes both immunological activation and inflammatory pathways, the exact cause of RA remains unclear. It seems however, that RA is initiated by a [...] Read more.
Rheumatoid Arthritis (RA) is among the most prevalent and impactful rheumatologic chronic autoimmune diseases (AIDs) worldwide. Within a framework that recognizes both immunological activation and inflammatory pathways, the exact cause of RA remains unclear. It seems however, that RA is initiated by a combination between genetic susceptibility, and environmental triggers, which result in an auto-perpetuating process. The subsequently, systemic inflammation associated with RA is linked with a variety of extra-articular comorbidities, including cardiovascular disease (CVD), resulting in increased mortality and morbidity. Hitherto, vast evidence demonstrated the key role of non-coding RNAs such as microRNAs (miRNAs) in RA, and in RA-CVD related complications. In this descriptive review, we aim to highlight the specific role of miRNAs in autoimmune processes, explicitly on their regulatory roles in the pathogenesis of RA, and its CV consequences, their main role as novel biomarkers, and their possible role as therapeutic targets. Full article
Show Figures

Figure 1

14 pages, 2557 KiB  
Article
MicroRNA-449a Inhibits Triple Negative Breast Cancer by Disturbing DNA Repair and Chromatid Separation
by Beate Vajen, Rahul Bhowmick, Luisa Greiwe, Vera Schäffer, Marlies Eilers, Thea Reinkens, Amelie Stalke, Gunnar Schmidt, Jan Fiedler, Thomas Thum, David S. DeLuca, Ian D. Hickson, Brigitte Schlegelberger, Thomas Illig and Britta Skawran
Int. J. Mol. Sci. 2022, 23(9), 5131; https://doi.org/10.3390/ijms23095131 - 04 May 2022
Cited by 1 | Viewed by 1954
Abstract
Chromosomal instability (CIN) can be a driver of tumorigenesis but is also a promising therapeutic target for cancer associated with poor prognosis such as triple negative breast cancer (TNBC). The treatment of TNBC cells with defects in DNA repair genes with poly(ADP-ribose) polymerase [...] Read more.
Chromosomal instability (CIN) can be a driver of tumorigenesis but is also a promising therapeutic target for cancer associated with poor prognosis such as triple negative breast cancer (TNBC). The treatment of TNBC cells with defects in DNA repair genes with poly(ADP-ribose) polymerase inhibitor (PARPi) massively increases CIN, resulting in apoptosis. Here, we identified a previously unknown role of microRNA-449a in CIN. The transfection of TNBC cell lines HCC38, HCC1937 and HCC1395 with microRNA-449a mimics led to induced apoptosis, reduced cell proliferation, and reduced expression of genes in homology directed repair (HDR) in microarray analyses. EME1 was identified as a new target gene by immunoprecipitation and luciferase assays. The reduced expression of EME1 led to an increased frequency of ultrafine bridges, 53BP1 foci, and micronuclei. The induced expression of microRNA-449a elevated CIN beyond tolerable levels and induced apoptosis in TNBC cell lines by two different mechanisms: (I) promoting chromatid mis-segregation by targeting endonuclease EME1 and (II) inhibiting HDR by downregulating key players of the HDR network such as E2F3, BIRC5, BRCA2 and RAD51. The ectopic expression of microRNA-449a enhanced the toxic effect of PARPi in cells with pathogenic germline BRCA1 variants. The newly identified role makes microRNA-449a an interesting therapeutic target for TNBC. Full article
Show Figures

Figure 1

15 pages, 3720 KiB  
Article
Exclusion of NUMB Exon12 Controls Cancer Cell Migration through Regulation of Notch1-SMAD3 Crosstalk
by Zheng Zhan, Ningyang Yuan, Xue You, Kai Meng, Rula Sha, Zhenzhen Wang, Qian Peng, Zhiqin Xie, Ruijiao Chen and Ying Feng
Int. J. Mol. Sci. 2022, 23(8), 4363; https://doi.org/10.3390/ijms23084363 - 14 Apr 2022
Cited by 1 | Viewed by 1677
Abstract
NUMB is an endocytic adaptor protein that contains four isoforms (p65, p66, p71 and p72) due to alternative splicing regulation. Here, we show that NUMB exon12 (E12)-skipping isoforms p65/p66 promote epithelial to mesenchymal transition (EMT) and cancer cell migration in vitro, and facilitate [...] Read more.
NUMB is an endocytic adaptor protein that contains four isoforms (p65, p66, p71 and p72) due to alternative splicing regulation. Here, we show that NUMB exon12 (E12)-skipping isoforms p65/p66 promote epithelial to mesenchymal transition (EMT) and cancer cell migration in vitro, and facilitate cancer metastasis in mice, whereas E12-included p71/p72 isoforms attenuate these effects. Mechanistically, p65/p66 isoforms significantly increase the sorting of Notch1 through early endosomes (EEs) for enhanced Notch1 activity. In contrast, p71/p72 isoforms act as negative regulators of Notch1 by ubiquitylating the Notch1 intracellular domain (N1ICD) and promoting its degradation. Moreover, we observed that the interaction between N1ICD and SMAD3 is important for their own stabilization, and for NUMB-mediated EMT response and cell migration. Either N1ICD or SMAD3 overexpression could significantly recuse the migration reduction seen in the p65/p66 knockdown, and Notch1 or SMAD3 knockdown rescued the migration advantage seen in the overexpression of p66. Taken all together, our study provides mechanistic insights into the opposite regulation of Notch1-SMAD3 crosstalk by NUMB isoforms and identifies them as critical regulators of EMT and cancer cell migration. Full article
Show Figures

Figure 1

2021

Jump to: 2023, 2022, 2020, 2019, 2018, 2017, 2016, 2015, 2014

16 pages, 5878 KiB  
Article
Novel and Annotated Long Noncoding RNAs Associated with Ischemia in the Human Heart
by Zoe Ward, Sebastian Schmeier, Louis Saddic, Martin I. Sigurdsson, Vicky A. Cameron, John Pearson, Allison Miller, Arthur Morley-Bunker, Josh Gorham, Jonathan G. Seidman, Christine S. Moravec, Wendy E. Sweet, Sary F. Aranki, Simon Body, Jochen D. Muehlschlegel and Anna P. Pilbrow
Int. J. Mol. Sci. 2021, 22(21), 11324; https://doi.org/10.3390/ijms222111324 - 20 Oct 2021
Cited by 4 | Viewed by 2392
Abstract
Background: Long noncoding RNAs (lncRNAs) have been implicated in the pathogenesis of cardiovascular diseases. We aimed to identify novel lncRNAs associated with the early response to ischemia in the heart. Methods and Results: RNA sequencing data gathered from 81 paired left ventricle samples [...] Read more.
Background: Long noncoding RNAs (lncRNAs) have been implicated in the pathogenesis of cardiovascular diseases. We aimed to identify novel lncRNAs associated with the early response to ischemia in the heart. Methods and Results: RNA sequencing data gathered from 81 paired left ventricle samples from patients undergoing cardiopulmonary bypass was collected before and after a period of ischemia. Novel lncRNAs were validated with Oxford Nanopore Technologies long-read sequencing. Gene modules associated with an early ischemic response were identified and the subcellular location of selected lncRNAs was determined with RNAscope. A total of 2446 mRNAs, 270 annotated lncRNAs and one novel lncRNA differed in response to ischemia (adjusted p < 0.001, absolute fold change >1.2). The novel lncRNA belonged to a gene module of highly correlated genes that also included 39 annotated lncRNAs. This module associated with ischemia (Pearson correlation coefficient = −0.69, p = 1 × 10−23) and activation of cell death pathways (p < 6 × 10−9). A further nine novel cardiac lncRNAs were identified, of which, one overlapped five cis-eQTL eSNPs for the gene RWD Domain-Containing Sumoylation Enhancer (RWDD3) and was itself correlated with RWDD3 expression (Pearson correlation coefficient −0.2, p = 0.002). Conclusion: We have identified 10 novel lncRNAs, one of which was associated with myocardial ischemia and may have potential as a novel therapeutic target or early marker for myocardial dysfunction. Full article
Show Figures

Figure 1

2020

Jump to: 2023, 2022, 2021, 2019, 2018, 2017, 2016, 2015, 2014

13 pages, 1087 KiB  
Review
The Role of Small Noncoding RNA in DNA Double-Strand Break Repair
by Iwona Rzeszutek and Gabriela Betlej
Int. J. Mol. Sci. 2020, 21(21), 8039; https://doi.org/10.3390/ijms21218039 - 28 Oct 2020
Cited by 11 | Viewed by 4018
Abstract
DNA damage is a common phenomenon promoted through a variety of exogenous and endogenous factors. The DNA damage response (DDR) pathway involves a wide range of proteins, and as was indicated, small noncoding RNAs (sncRNAs). These are double-strand break-induced RNAs (diRNAs) and DNA [...] Read more.
DNA damage is a common phenomenon promoted through a variety of exogenous and endogenous factors. The DNA damage response (DDR) pathway involves a wide range of proteins, and as was indicated, small noncoding RNAs (sncRNAs). These are double-strand break-induced RNAs (diRNAs) and DNA damage response small RNA (DDRNA). Moreover, RNA binding proteins (RBPs) and RNA modifications have also been identified to modulate diRNA and DDRNA function in the DDR process. Several theories have been formulated regarding the synthesis and function of these sncRNAs during DNA repair; nevertheless, these pathways’ molecular details remain unclear. Here, we review the current knowledge regarding the mechanisms of diRNA and DDRNA biosynthesis and discuss the role of sncRNAs in maintaining genome stability. Full article
Show Figures

Figure 1

19 pages, 1475 KiB  
Review
Non-Coding RNAs as Potential Novel Biomarkers for Early Diagnosis of Hepatic Insulin Resistance
by Ariadna Pielok and Krzysztof Marycz
Int. J. Mol. Sci. 2020, 21(11), 4182; https://doi.org/10.3390/ijms21114182 - 11 Jun 2020
Cited by 20 | Viewed by 3742
Abstract
In the recent years, the prevalence of metabolic conditions such as type 2 Diabetes (T2D) and metabolic syndrome (MetS) raises. The impairment of liver metabolism resulting in hepatic insulin resistance is a common symptom and a critical step in the development of T2D [...] Read more.
In the recent years, the prevalence of metabolic conditions such as type 2 Diabetes (T2D) and metabolic syndrome (MetS) raises. The impairment of liver metabolism resulting in hepatic insulin resistance is a common symptom and a critical step in the development of T2D and MetS. The liver plays a crucial role in maintaining glucose homeostasis. Hepatic insulin resistance can often be identified before other symptoms arrive; therefore, establishing methods for its early diagnosis would allow for the implementation of proper treatment in patients before the disease develops. Non-coding RNAs such as miRNAs (micro-RNA) and lncRNAs (long-non-coding RNA) are being recognized as promising novel biomarkers and therapeutic targets—especially due to their regulatory function. The dysregulation of miRNA and lncRNA activity has been reported in the livers of insulin-resistant patients. Many of those transcripts are involved in the regulation of the hepatic insulin signaling cascade. Furthermore, for several miRNAs (miR-802, miR-499-5p, and miR-122) and lncRNAs (H19 imprinted maternally expressed transcript (H19), maternally expressed gene 3 (MEG3), and metastasis associated lung adenocarcinoma transcript 1 (MALAT1)), circulating levels were altered in patients with prediabetes, T2D, and MetS. In the course of this review, the role of the aforementioned ncRNAs in hepatic insulin signaling cascade, as well as their potential application in diagnostics, is discussed. Overall, circulating ncRNAs are precise indicators of hepatic insulin resistance in the development of metabolic diseases and could be applied as early diagnostic and/or therapeutic tools in conditions associated with insulin resistance. Full article
Show Figures

Figure 1

12 pages, 1378 KiB  
Article
microRNAs in Ex Vivo Human Adipose Tissue Derived Mesenchymal Stromal Cells (ASC) Undergo Rapid Culture-Induced Changes in Expression, Including miR-378 which Promotes Adipogenesis
by Megan Iminitoff, Tanvi Damani, Eloise Williams, Anna E. S. Brooks, Vaughan Feisst and Hilary M. Sheppard
Int. J. Mol. Sci. 2020, 21(4), 1492; https://doi.org/10.3390/ijms21041492 - 21 Feb 2020
Cited by 3 | Viewed by 2630
Abstract
There is clinical interest in using human adipose tissue-derived mesenchymal stromal cells (ASC) to treat a range of inflammatory and regenerative conditions. Aspects of ASC biology, including their regenerative potential and paracrine effect, are likely to be modulated, in part, by microRNAs, small [...] Read more.
There is clinical interest in using human adipose tissue-derived mesenchymal stromal cells (ASC) to treat a range of inflammatory and regenerative conditions. Aspects of ASC biology, including their regenerative potential and paracrine effect, are likely to be modulated, in part, by microRNAs, small RNA molecules that are embedded as regulators of gene-expression in most biological pathways. However, the effect of standard isolation and expansion protocols on microRNA expression in ASC is not well explored. Here, by using an untouched and enriched population of primary human ASC, we demonstrate that there are rapid and significant changes in microRNA expression when ASC are subjected to standard isolation and expansion methods. Functional studies focusing on miR-378 indicate that these changes in expression may have an impact on phenotype and function. Specifically, we found that increased levels of miR-378 significantly promoted adipogenesis in late passage ASC. These results are informative to maximizing the potential of ASC for use in various clinical applications, and they have implications for targeting microRNAs as a therapeutic strategy for obesity or metabolic disease. Full article
Show Figures

Figure 1

2019

Jump to: 2023, 2022, 2021, 2020, 2018, 2017, 2016, 2015, 2014

18 pages, 1732 KiB  
Review
Emerging Role of Non-Coding RNAs in Esophageal Squamous Cell Carcinoma
by Qingqing Feng, Hongli Zhang, Denglin Yao, Wei-Dong Chen and Yan-Dong Wang
Int. J. Mol. Sci. 2020, 21(1), 258; https://doi.org/10.3390/ijms21010258 - 30 Dec 2019
Cited by 55 | Viewed by 3837
Abstract
Esophageal squamous cell carcinoma (ESCC) is a highly prevalent tumor and is associated with ethnicity, genetics, and dietary intake. Non-coding RNAs (ncRNAs), specifically microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs) have been reported as functional regulatory molecules involved in the development [...] Read more.
Esophageal squamous cell carcinoma (ESCC) is a highly prevalent tumor and is associated with ethnicity, genetics, and dietary intake. Non-coding RNAs (ncRNAs), specifically microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs) have been reported as functional regulatory molecules involved in the development of many human cancers, including ESCC. Recently, several ncRNAs have been detected as oncogenes or tumor suppressors in ESCC progression. These ncRNAs influence the expression of specific genes or their associated signaling pathways. Moreover, interactions of ncRNAs are evident in ESCC, as miRNAs regulate the expression of lncRNAs, and further, lncRNAs and circRNAs function as miRNA sponges to compete with the endogenous RNAs. Here, we discuss and summarize the findings of recent investigations into the role of ncRNAs (miRNAs, lncRNAs, and circRNAs) in the development and progression of ESCC and how their interactions regulate ESCC development. Full article
Show Figures

Figure 1

29 pages, 3124 KiB  
Review
Mechanisms and Functions of Long Non-Coding RNAs at Multiple Regulatory Levels
by Xiaopei Zhang, Wei Wang, Weidong Zhu, Jie Dong, Yingying Cheng, Zujun Yin and Fafu Shen
Int. J. Mol. Sci. 2019, 20(22), 5573; https://doi.org/10.3390/ijms20225573 - 08 Nov 2019
Cited by 454 | Viewed by 13237
Abstract
Long non-coding (lnc) RNAs are non-coding RNAs longer than 200 nt. lncRNAs primarily interact with mRNA, DNA, protein, and miRNA and consequently regulate gene expression at the epigenetic, transcriptional, post-transcriptional, translational, and post-translational levels in a variety of ways. They play important roles [...] Read more.
Long non-coding (lnc) RNAs are non-coding RNAs longer than 200 nt. lncRNAs primarily interact with mRNA, DNA, protein, and miRNA and consequently regulate gene expression at the epigenetic, transcriptional, post-transcriptional, translational, and post-translational levels in a variety of ways. They play important roles in biological processes such as chromatin remodeling, transcriptional activation, transcriptional interference, RNA processing, and mRNA translation. lncRNAs have important functions in plant growth and development; biotic and abiotic stress responses; and in regulation of cell differentiation, the cell cycle, and the occurrence of many diseases in humans and animals. In this review, we summarize the functions and mechanisms of lncRNAs in plants, humans, and animals at different regulatory levels. Full article
Show Figures

Graphical abstract

27 pages, 1211 KiB  
Review
The Regulatory Role of MicroRNAs in Breast Cancer
by Hui-Yi Loh, Brendan P. Norman, Kok-Song Lai, Nik Mohd Afizan Nik Abd. Rahman, Noorjahan Banu Mohamed Alitheen and Mohd Azuraidi Osman
Int. J. Mol. Sci. 2019, 20(19), 4940; https://doi.org/10.3390/ijms20194940 - 06 Oct 2019
Cited by 200 | Viewed by 17481
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules which function as critical post-transcriptional gene regulators of various biological functions. Generally, miRNAs negatively regulate gene expression by binding to their selective messenger RNAs (mRNAs), thereby leading to either mRNA degradation or translational repression, depending on [...] Read more.
MicroRNAs (miRNAs) are small non-coding RNA molecules which function as critical post-transcriptional gene regulators of various biological functions. Generally, miRNAs negatively regulate gene expression by binding to their selective messenger RNAs (mRNAs), thereby leading to either mRNA degradation or translational repression, depending on the degree of complementarity with target mRNA sequences. Aberrant expression of these miRNAs has been linked etiologically with various human diseases including breast cancer. Different cellular pathways of breast cancer development such as cell proliferation, apoptotic response, metastasis, cancer recurrence and chemoresistance are regulated by either the oncogenic miRNA (oncomiR) or tumor suppressor miRNA (tsmiR). In this review, we highlight the current state of research into miRNA involved in breast cancer, with particular attention to articles published between the years 2000 to 2019, using detailed searches of the databases PubMed, Google Scholar, and Scopus. The post-transcriptional gene regulatory roles of various dysregulated miRNAs in breast cancer and their potential as therapeutic targets are also discussed. Full article
Show Figures

Graphical abstract

12 pages, 2223 KiB  
Article
Rolling Circle cDNA Synthesis Uncovers Circular RNA Splice Variants
by Aniruddha Das, Pranita K. Rout, Myriam Gorospe and Amaresh C. Panda
Int. J. Mol. Sci. 2019, 20(16), 3988; https://doi.org/10.3390/ijms20163988 - 16 Aug 2019
Cited by 20 | Viewed by 7192
Abstract
High-throughput RNA sequencing and novel bioinformatic pipelines have identified thousands of circular (circ)RNAs containing backsplice junction sequences. However, circRNAs generated from multiple exons may contain different combinations of exons and/or introns arising from alternative splicing, while the backsplice junction sequence is the same. [...] Read more.
High-throughput RNA sequencing and novel bioinformatic pipelines have identified thousands of circular (circ)RNAs containing backsplice junction sequences. However, circRNAs generated from multiple exons may contain different combinations of exons and/or introns arising from alternative splicing, while the backsplice junction sequence is the same. To be able to identify circRNA splice variants, we developed a method termed circRNA-Rolling Circle Amplification (circRNA-RCA). This method detects full-length circRNA sequences by performing reverse transcription (RT) in the absence of RNase H activity, followed by polymerase chain reaction (PCR) amplification of full-length circRNAs using a forward primer spanning the backsplice junction sequence and a reverse primer exactly upstream of the forward primer. By sequencing the PCR products, circRNA splice variants bearing the same backsplice junctions, which were otherwise only predicted computationally, could be experimentally validated. The splice variants were further predicted to associate with different subsets of target RNA-binding proteins and microRNAs, supporting the notion that different circRNA splice variants can have different biological impacts. In sum, the circRNA-RCA method allows the accurate identification of full-length circRNA sequences, offering unique insight into their individual function. Full article
Show Figures

Figure 1

20 pages, 418 KiB  
Review
LncRNAs Regulatory Networks in Cellular Senescence
by Pavan Kumar Puvvula
Int. J. Mol. Sci. 2019, 20(11), 2615; https://doi.org/10.3390/ijms20112615 - 28 May 2019
Cited by 65 | Viewed by 4990
Abstract
Long noncoding RNAs (lncRNAs) are a class of transcripts longer than 200 nucleotides with no open reading frame. They play a key role in the regulation of cellular processes such as genome integrity, chromatin organization, gene expression, translation regulation, and signal transduction. Recent [...] Read more.
Long noncoding RNAs (lncRNAs) are a class of transcripts longer than 200 nucleotides with no open reading frame. They play a key role in the regulation of cellular processes such as genome integrity, chromatin organization, gene expression, translation regulation, and signal transduction. Recent studies indicated that lncRNAs are not only dysregulated in different types of diseases but also function as direct effectors or mediators for many pathological symptoms. This review focuses on the current findings of the lncRNAs and their dysregulated signaling pathways in senescence. Different functional mechanisms of lncRNAs and their downstream signaling pathways are integrated to provide a bird’s-eye view of lncRNA networks in senescence. This review not only highlights the role of lncRNAs in cell fate decision but also discusses how several feedback loops are interconnected to execute persistent senescence response. Finally, the significance of lncRNAs in senescence-associated diseases and their therapeutic and diagnostic potentials are highlighted. Full article
Show Figures

Figure 1

13 pages, 2192 KiB  
Article
Circulating miRNA Signature as a Potential Biomarker for the Prediction of Analgesic Efficacy of Hydromorphone
by Naoki Kiyosawa, Kenji Watanabe, Kaoru Toyama and Hitoshi Ishizuka
Int. J. Mol. Sci. 2019, 20(7), 1665; https://doi.org/10.3390/ijms20071665 - 03 Apr 2019
Cited by 11 | Viewed by 3337
Abstract
No practical biomarkers currently exist for the prediction of the analgesic efficacy of opioids. Previously, we reported circulating miRNA signatures differentially regulated by µ-opioid receptor (MOR) agonists in healthy subjects. We hypothesized that these miRNAs could be potential pharmacodynamic biomarkers to estimate MOR [...] Read more.
No practical biomarkers currently exist for the prediction of the analgesic efficacy of opioids. Previously, we reported circulating miRNA signatures differentially regulated by µ-opioid receptor (MOR) agonists in healthy subjects. We hypothesized that these miRNAs could be potential pharmacodynamic biomarkers to estimate MOR stimulation, and predict the efficacy of opioids; i.e., patients with low MOR stimulation may be more vulnerable to strengthening of the MOR signal upon hydromorphone treatment. To test this hypothesis, plasma samples were obtained from 25 patients with cancer pain prior to the initiation of hydromorphone treatment and the circulating miRNA levels were evaluated, focusing on four miRNAs (i.e., hsa-miR-423-3p, hsa-let-7a-5p, hsa-miR-26a-5p, and hsa-let-7f-5p) and four miRNAs (i.e., hsa-miR-144-3p, hsa-miR-451a, hsa-miR-215, and hsa-miR-363-3p) that were most clearly up and downregulated by hydromorphone and oxycodone. The patients were classified into two classes with putative high and low MOR signal, estimated based on the plasma miRNA signature. A significant correlation was observed between the analgesic efficacy and the putative MOR signal level, and patients with low MOR signal achieved better pain control (i.e., ΔVAS < 0) through hydromorphone. These results suggested that plasma miRNA signatures could serve as clinical biomarkers for the prediction of the analgesic efficacy of hydromorphone. Full article
Show Figures

Figure 1

11 pages, 2382 KiB  
Article
MicroRNA Let-7d-3p Contributes to Cardiac Protection via Targeting HMGA2
by Lee Lee Wong, Eng Leng Saw, Jia Yuen Lim, Yue Zhou, Arthur Mark Richards and Peipei Wang
Int. J. Mol. Sci. 2019, 20(7), 1522; https://doi.org/10.3390/ijms20071522 - 27 Mar 2019
Cited by 15 | Viewed by 3631
Abstract
We tested the hypothesis that Let-7d-3p contributes to cardiac cell protection during hypoxic challenge. Myoblast H9c2 cells and primary neonatal rat ventricular cardiomyocytes (NRVM) were transfected with five selected miRNA mimics. Both cell lines were subjected to 0.2% oxygen hypoxia. The protective effects [...] Read more.
We tested the hypothesis that Let-7d-3p contributes to cardiac cell protection during hypoxic challenge. Myoblast H9c2 cells and primary neonatal rat ventricular cardiomyocytes (NRVM) were transfected with five selected miRNA mimics. Both cell lines were subjected to 0.2% oxygen hypoxia. The protective effects of these miRNAs were determined by assessment of cell metabolic activity by CCK8 assay and measurement of lactate dehydrogenase (LDH) release as a marker of cell injury. Apoptosis and autophagy flux were assessed by Annexin V/7-AAD double staining and the ratio of LC3 II/I with Baf-A1 treatment, an autophagy flux inhibitor, respectively. Luciferase-reporter assay, RT-qPCR and Western blots were performed to identify the changes of relevant gene targets. Among five miRNA mimic transfections, Let-7d-3p increased CCK8 activity, and decreased LDH release in both H9c2 and NRVM during hypoxia. Apoptosis was significantly reduced in H9c2 cells transfected with Let-7d-3p mimic. Autophagy and autophagy flux were not affected. In silico, mRNAs of HMGA2, YY1, KLF9, KLF12, and MEX3C are predicted targets for Let-7d-3p. Luciferase-reporter assay confirmed that Let-7d-3p bound directly to the 3’-UTR region of HMGA2, MEX3C, and YY1, the down-regulations of these mRNAs were verified in both H9c2 and NRVM. The protein expression of HMGA2, but not others, was downregulated in H9c2 and NRVM. It is known that HMGA2 is a strong apoptosis trigger through the blocking of DNA repair. Thus, we speculate that the anti-apoptotic effects of Let-7d-3p mimic during hypoxia challenge are due to direct targeting of HMGA2. Full article
Show Figures

Figure 1

16 pages, 4940 KiB  
Article
Upregulated gga-miR-16-5p Inhibits the Proliferation Cycle and Promotes the Apoptosis of MG-Infected DF-1 Cells by Repressing PIK3R1-Mediated the PI3K/Akt/NF-κB Pathway to Exert Anti-Inflammatory Effect
by Kang Zhang, Yun Han, Yabo Zhao, Yingfei Sun, Mengyun Zou, Yali Fu and Xiuli Peng
Int. J. Mol. Sci. 2019, 20(5), 1036; https://doi.org/10.3390/ijms20051036 - 27 Feb 2019
Cited by 22 | Viewed by 3179
Abstract
Mycoplasma gallisepticum (MG) mainly infects chickens to initiate chronic respiratory disease (CRD). microRNAs (miRNAs) play vital roles according to previously reported studies. Our previous study showed that gga-miR-16-5p, in MG-infected lungs of chicken embryo, was upregulated by Illumina sequencing. The [...] Read more.
Mycoplasma gallisepticum (MG) mainly infects chickens to initiate chronic respiratory disease (CRD). microRNAs (miRNAs) play vital roles according to previously reported studies. Our previous study showed that gga-miR-16-5p, in MG-infected lungs of chicken embryo, was upregulated by Illumina sequencing. The study aimed to reveal what role gga-miR-16-5p plays in CRD progression. gga-miR-16-5p was upregulated in MG-infected fibroblast cells (DF-1). Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) was demonstrated as the target gene of gga-miR-16-5p. Furthermore, PIK3R1 expression was lower in MG-infected groups than it in noninfected controls measured by qPCR. Additionally, overexpressed gga-miR-16-5p could downregulate PIK3R1 and phosphorylated serine/threonine kinase (p-Akt) to express protein, whereas there is an opposite effect on inhibition. Overexpressed gga-miR-16-5p resulted in decreased activity of tumor necrosis factor alpha (TNF-α) and the nuclear factor-kappaB (NF-κB) by qPCR. Furthermore, overexpressed gga-miR-16-5p restricted cell multiplication, cycle progression, and increased apoptosis of MG-infected DF-1 cells, whereas inhibited gga-miR-16-5p led to the opposite effect. Collectively, upregulated gga-miR-16-5p could decrease multiplication, cycle progression, and increase apoptosis of MG-infected DF-1 cells, at least partly through directly targeting PIK3R1 and inhibiting PI3K/Akt/NF-κB pathway to exert an anti-inflammatory effect. Our results will provide more experimental evidence to bring pathogenesis of MG infection to light. Full article
Show Figures

Figure 1

17 pages, 1475 KiB  
Review
The Implications of the Long Non-Coding RNA NEAT1 in Non-Cancerous Diseases
by Felix Prinz, Anita Kapeller, Martin Pichler and Christiane Klec
Int. J. Mol. Sci. 2019, 20(3), 627; https://doi.org/10.3390/ijms20030627 - 01 Feb 2019
Cited by 68 | Viewed by 7725
Abstract
Long non-coding RNAs (lncRNAs) are involved in a variety of biological and cellular processes as well as in physiologic and pathophysiologic events. This review summarizes recent literature about the role of the lncRNA nuclear enriched abundant transcript 1 (NEAT1) in non-cancerous [...] Read more.
Long non-coding RNAs (lncRNAs) are involved in a variety of biological and cellular processes as well as in physiologic and pathophysiologic events. This review summarizes recent literature about the role of the lncRNA nuclear enriched abundant transcript 1 (NEAT1) in non-cancerous diseases with a special focus on viral infections and neurodegenerative diseases. In contrast to its role as competing endogenous RNA (ceRNA) in carcinogenesis, NEAT1’s function in non-cancerous diseases predominantly focuses on paraspeckle-mediated effects on gene expression. This involves processes such as nuclear retention of mRNAs or sequestration of paraspeckle proteins from specific promoters, resulting in transcriptional induction or repression of genes involved in regulating the immune system or neurodegenerative processes. NEAT1 expression is aberrantly—mostly upregulated—in non-cancerous pathological conditions, indicating that it could serve as potential prognostic biomarker. Additional studies are needed to elucidate NEAT1’s capability to be a therapeutic target for non-cancerous diseases. Full article
Show Figures

Graphical abstract

22 pages, 5783 KiB  
Article
5p and 3p Strands of miR-34 Family Members Have Differential Effects in Cell Proliferation, Migration, and Invasion in Cervical Cancer Cells
by Sergio Córdova-Rivas, Ixamail Fraire-Soto, Andrea Mercado-Casas Torres, Luis Steven Servín-González, Angelica Judith Granados-López, Yamilé López-Hernández, Claudia Araceli Reyes-Estrada, Rosalinda Gutiérrez-Hernández, Julio Enrique Castañeda-Delgado, Leticia Ramírez-Hernández, José Antonio Varela-Silva and Jesús Adrián López
Int. J. Mol. Sci. 2019, 20(3), 545; https://doi.org/10.3390/ijms20030545 - 28 Jan 2019
Cited by 40 | Viewed by 5039
Abstract
The micro RNA (miR)-34 family is composed of 5p and 3p strands of miR-34a, miR-34b, and miR-34c. The 5p strand’s expression and function is studied in cervical cancer. The 3p strand’s function and regulation remain to be elucidated. To study the function of [...] Read more.
The micro RNA (miR)-34 family is composed of 5p and 3p strands of miR-34a, miR-34b, and miR-34c. The 5p strand’s expression and function is studied in cervical cancer. The 3p strand’s function and regulation remain to be elucidated. To study the function of the passenger strands of miR-34 family members, we overexpressed 5p and 3p strands using a synthetic miRNA in cervical cell lines. Cell proliferation was evaluated using crystal violet. Migration and invasion were tested using transwell assays, Western blot, and zymography. Possible specific targets and cell signaling were investigated for each strand. We found that miR-34a-5p inhibited proliferation, migration, and cell invasion accompanied by matrix metalloproteinase 9 (MMP9) activity and microtubule-associated protein 2 (MAP2) protein reduction. We also found that miR-34b-5p and miR-34c-5p inhibit proliferation and migration, but not invasion. In contrast, miR-34c-5p inhibits MMP9 activity and MAP2 protein, while miR-34b-5p has no effect on these genes. Furthermore, miR-34a-3p and miR-34b-3p inhibit proliferation and migration, but not invasion, despite the later reducing MMP2 activity, while miR-34c-3p inhibit proliferation, migration, and cell invasion accompanied by MMP9 activity and MAP2 protein inhibition. The difference in cellular processes, MMP2 and MMP9 activity, and MAP2 protein inhibition by miR-34 family members suggests the participation of other regulated genes. This study provides insights into the roles of passenger strands (strand*) of the miR-34 family in cervical cancer. Full article
Show Figures

Figure 1

2018

Jump to: 2023, 2022, 2021, 2020, 2019, 2017, 2016, 2015, 2014

11 pages, 1290 KiB  
Article
MiR-371a-3p Serum Levels Are Increased in Recurrence of Testicular Germ Cell Tumor Patients
by Angelika Terbuch, Jan B. Adiprasito, Verena Stiegelbauer, Maximilian Seles, Christiane Klec, Georg P. Pichler, Margit Resel, Florian Posch, Anna L. Lembeck, Herbert Stöger, Joanna Szkandera, Karl Pummer, Thomas Bauernhofer, Georg C. Hutterer, Armin Gerger, Michael Stotz and Martin Pichler
Int. J. Mol. Sci. 2018, 19(10), 3130; https://doi.org/10.3390/ijms19103130 - 12 Oct 2018
Cited by 44 | Viewed by 4224
Abstract
Metastatic testicular germ cell tumors (TGCTs) are a potentially curable disease by administration of risk-adapted cytotoxic chemotherapy. Nevertheless, a disease-relapse after curative chemotherapy needs more intensive salvage chemotherapy and significantly worsens the prognosis of TGCT patients. Circulating tumor markers (β-subunit of human chorionic [...] Read more.
Metastatic testicular germ cell tumors (TGCTs) are a potentially curable disease by administration of risk-adapted cytotoxic chemotherapy. Nevertheless, a disease-relapse after curative chemotherapy needs more intensive salvage chemotherapy and significantly worsens the prognosis of TGCT patients. Circulating tumor markers (β-subunit of human chorionic gonadotropin (β-HCG), alpha-Fetoprotein (AFP), and Lactate Dehydrogenase (LDH)) are frequently used for monitoring disease recurrence in TGCT patients, though they lack diagnostic sensitivity and specificity. Increasing evidence suggests that serum levels of stem cell-associated microRNAs (miR-371a-3p and miR-302/367 cluster) are outperforming the traditional tumor markers in terms of sensitivity to detect newly diagnosed TGCT patients. The aim of this study was to investigate whether these miRNAs are also informative in detection of disease recurrence in TGCT patients after curative first line therapy. For this purpose, we measured the serum levels of miR-371a-3p and miR-367 in 52 samples of ten TGCT patients at different time points during disease relapse and during salvage chemotherapy. In our study, miR-371a-3p levels in serum samples with proven disease recurrence were 13.65 fold higher than levels from the same patients without evidence of disease (p = 0.014). In contrast, miR-367 levels were not different in these patient groups (p = 0.985). In conclusion, miR-371a-3p is a sensitive and potentially novel biomarker for detecting disease relapse in TGCT patients. This promising biomarker should be investigated in further large prospective trials. Full article
Show Figures

Figure 1

17 pages, 2048 KiB  
Article
Transcriptome Sequencing Reveals the Differentially Expressed lncRNAs and mRNAs Involved in Cryoinjuries in Frozen-Thawed Giant Panda (Ailuropoda melanoleuca) Sperm
by Ming-Xia Ran, Yuan Li, Yan Zhang, Kai Liang, Ying-Nan Ren, Ming Zhang, Guang-Bin Zhou, Ying-Min Zhou, Kai Wu, Cheng-Dong Wang, Yan Huang, Bo Luo, Izhar Hyder Qazi, He-Min Zhang and Chang-Jun Zeng
Int. J. Mol. Sci. 2018, 19(10), 3066; https://doi.org/10.3390/ijms19103066 - 08 Oct 2018
Cited by 20 | Viewed by 4172
Abstract
Sperm cryopreservation and artificial insemination are important methods for giant panda breeding and preservation of extant genetic diversity. Lower conception rates limit the use of artificial insemination with frozen-thawed giant panda sperm, due to the lack of understanding of the cryodamaging or cryoinjuring [...] Read more.
Sperm cryopreservation and artificial insemination are important methods for giant panda breeding and preservation of extant genetic diversity. Lower conception rates limit the use of artificial insemination with frozen-thawed giant panda sperm, due to the lack of understanding of the cryodamaging or cryoinjuring mechanisms in cryopreservation. Long non-coding RNAs (lncRNAs) are involved in regulating spermatogenesis. However, their roles during cryopreservation remain largely unexplored. Therefore, this study aimed to identify differentially expressed lncRNAs and mRNAs associated with cryodamage or freeze tolerance in frozen-thawed sperm through high throughput sequencing. A total of 61.05 Gb clean reads and 22,774 lncRNA transcripts were obtained. From the sequencing results, 1477 significantly up-regulated and 1,396 significantly down-regulated lncRNA transcripts from fresh and frozen-thawed sperm of giant panda were identified. GO and KEGG showed that the significantly dysregulated lncRNAs and mRNAs were mainly involved in regulating responses to cold stress and apoptosis, such as the integral component of membrane, calcium transport, and various signaling pathways including PI3K-Akt, p53 and cAMP. Our work is the first systematic profiling of lncRNA and mRNA in fresh and frozen-thawed giant panda sperm, and provides valuableinsights into the potential mechanism of cryodamage in sperm. Full article
Show Figures

Graphical abstract

11 pages, 2868 KiB  
Article
Circulating Serum miRNA-205 as a Diagnostic Biomarker for Ototoxicity in Mice Treated with Aminoglycoside Antibiotics
by Sun Hee Lee, Hyun Mi Ju, Jin Sil Choi, Yeji Ahn, Suhun Lee and Young Joon Seo
Int. J. Mol. Sci. 2018, 19(9), 2836; https://doi.org/10.3390/ijms19092836 - 19 Sep 2018
Cited by 14 | Viewed by 3884
Abstract
Background: To confirm levels and detection timing of circulating microRNAs (miRNAs) in the serum of a mouse model for diagnosis of ototoxicity, circulating miR-205 in the serum was evaluated to reflect damages in the cochlear microstructure and compared to a kidney injury model. [...] Read more.
Background: To confirm levels and detection timing of circulating microRNAs (miRNAs) in the serum of a mouse model for diagnosis of ototoxicity, circulating miR-205 in the serum was evaluated to reflect damages in the cochlear microstructure and compared to a kidney injury model. Method: A microarray for miRNAs in the serum was performed to assess the ototoxic effects of kanamycin-furosemide. Changes in the levels for the selected miRNAs (miR-205, miR-183, and miR-103) were compared in the serum and microstructures of the cochlea (stria vascularis, organ of Corti, and modiolus) between the ototoxicity and normal mouse groups. An acute kidney injury (AKI) mouse model was used to assess changes in miR-205 levels in the kidney by ototoxic drugs. Results: In the mouse model for ototoxicity, the serum levels of circulating miR-205 peaked on day 3 and were sustained from days 7–14. Furthermore, miR-205 expression was highly expressed in the organ of Corti at day 5, continued to be expressed in the modiolus at high levels until day 14, and was finally also in the stria vascularis. The serum miR-205 in the AKI mice did not change significantly compared to the normal group. Conclusions Circulating miR-205 from the cochlea, after ototoxic damage, migrates through the blood vessels to organs, which is then finally found in blood. In conditions of hearing impairment with ototoxic medications, detection of circulating miR-205 in the blood can be used to determine the extent of hearing loss. In the future, inner ear damage can be identified by simply performing a blood test before the hearing impairment due to ototoxic drugs. Full article
Show Figures

Figure 1

15 pages, 1353 KiB  
Review
Long Non-Coding RNAs in Gliomas: From Molecular Pathology to Diagnostic Biomarkers and Therapeutic Targets
by Marek Vecera, Jiri Sana, Radim Lipina, Martin Smrcka and Ondrej Slaby
Int. J. Mol. Sci. 2018, 19(9), 2754; https://doi.org/10.3390/ijms19092754 - 13 Sep 2018
Cited by 33 | Viewed by 4232
Abstract
Gliomas are the most common malignancies of the central nervous system. Because of tumor localization and the biological behavior of tumor cells, gliomas are characterized by very poor prognosis. Despite significant efforts that have gone into glioma research in recent years, the therapeutic [...] Read more.
Gliomas are the most common malignancies of the central nervous system. Because of tumor localization and the biological behavior of tumor cells, gliomas are characterized by very poor prognosis. Despite significant efforts that have gone into glioma research in recent years, the therapeutic efficacy of available treatment options is still limited, and only a few clinically usable diagnostic biomarkers are available. More and more studies suggest non-coding RNAs to be promising diagnostic biomarkers and therapeutic targets in many cancers, including gliomas. One of the largest groups of these molecules is long non-coding RNAs (lncRNAs). LncRNAs show promising potential because of their unique tissue expression patterns and regulatory functions in cancer cells. Understanding the role of lncRNAs in gliomas may lead to discovery of the novel molecular mechanisms behind glioma biological features. It may also enable development of new solutions to overcome the greatest obstacles in therapy of glioma patients. In this review, we summarize the current knowledge about lncRNAs and their involvement in the molecular pathology of gliomas. A conclusion follows that these RNAs show great potential to serve as powerful diagnostic, prognostic, and predictive biomarkers as well as therapeutic targets. Full article
Show Figures

Figure 1

12 pages, 450 KiB  
Review
Aberrant Regulation of mRNA m6A Modification in Cancer Development
by Junyun Luo, Hui Liu, Siyu Luan, Chongsheng He and Zhaoyong Li
Int. J. Mol. Sci. 2018, 19(9), 2515; https://doi.org/10.3390/ijms19092515 - 25 Aug 2018
Cited by 43 | Viewed by 7496
Abstract
N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic messenger RNAs (mRNAs). The m6A modification in RNA can be catalyzed by methyltransferases, or removed by demethylases, which are termed m6A writers and erasers, respectively. [...] Read more.
N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic messenger RNAs (mRNAs). The m6A modification in RNA can be catalyzed by methyltransferases, or removed by demethylases, which are termed m6A writers and erasers, respectively. Selective recognition and binding by distinct m6A reader proteins lead mRNA to divergent destinies. m6A has been reported to influence almost every stage of mRNA metabolism and to regulate multiple biological processes. Accumulating evidence strongly supports the correlation between aberrant cellular m6A level and cancer. We summarize here that deregulation of m6A modification, resulting from aberrant expression or function of m6A writers, erasers, readers or some other protein factors, is associated with carcinogenesis and cancer progression. Understanding the regulation and functional mechanism of mRNA m6A modification in cancer development may help in developing novel and efficient strategies for the diagnosis, prognosis and treatment of human cancers. Full article
Show Figures

Figure 1

13 pages, 5149 KiB  
Article
LncRNA ITGB2-AS1 Could Promote the Migration and Invasion of Breast Cancer Cells through Up-Regulating ITGB2
by Mengyao Liu, Liyao Gou, Jing Xia, Qun Wan, Yayun Jiang, Shilei Sun, Min Tang, Tongchuan He and Yan Zhang
Int. J. Mol. Sci. 2018, 19(7), 1866; https://doi.org/10.3390/ijms19071866 - 25 Jun 2018
Cited by 56 | Viewed by 4357
Abstract
In the previous study, we screened a novel lncRNA-ITGB2-AS1, which was down-regulated by bone morphogenetic protein 9 (BMP9) in breast cancer cell. Studying ITGB2-AS1 will lay the foundation for the exploring mechanism of the BMP9 inhibitory effect on breast cancer. The expression analysis [...] Read more.
In the previous study, we screened a novel lncRNA-ITGB2-AS1, which was down-regulated by bone morphogenetic protein 9 (BMP9) in breast cancer cell. Studying ITGB2-AS1 will lay the foundation for the exploring mechanism of the BMP9 inhibitory effect on breast cancer. The expression analysis related to ITGB2-AS1 in clinical samples was conducted on online websites. The overexpression plasmid or siRNA fragment was transfected into breast cancer cells to alter its gene expression. The MTT assay and flow cytometry were used to measure cell viability and cell cycle. Additionally, cell migration and invasion were detected by wound healing and transwell assay. The results of biological function experiments showed that ITGB2-AS1 could promote the migration and invasion of breast cancer. Furthermore, ITGB2-AS1 increased the mRNA and protein expression of ITGB2. Consistent with ITGB2-AS1, ITGB2 exerted the promotion effect on the migration and invasion of breast cancer and activated integrin-related FAK signaling. The OL plasmid expressing the truncation of ITGB2-AS1, which was complementary to ITGB2, was essential for activation of FAK signaling. In conclusion, LncRNA ITGB2-AS1 could promote the migration and invasion of breast cancer cells by up-regulating ITGB2. Full article
Show Figures

Figure 1

15 pages, 2943 KiB  
Article
Long Non-Coding RNA Malat1 Regulates Angiogenesis in Hindlimb Ischemia
by Xuejing Zhang, Xuelian Tang, Milton H. Hamblin and Ke-Jie Yin
Int. J. Mol. Sci. 2018, 19(6), 1723; https://doi.org/10.3390/ijms19061723 - 11 Jun 2018
Cited by 55 | Viewed by 5149
Abstract
Angiogenesis is a complex process that depends on the delicate regulation of gene expression. Dysregulation of transcription during angiogenesis often leads to various human diseases. Emerging evidence has recently begun to show that long non-coding RNAs (lncRNAs) may mediate angiogenesis in both physiological [...] Read more.
Angiogenesis is a complex process that depends on the delicate regulation of gene expression. Dysregulation of transcription during angiogenesis often leads to various human diseases. Emerging evidence has recently begun to show that long non-coding RNAs (lncRNAs) may mediate angiogenesis in both physiological and pathological conditions; concurrently, underlying molecular mechanisms are largely unexplored. Previously, our lab identified metastasis associates lung adenocarcinoma transcript 1 (Malat1) as an oxygen-glucose deprivation (OGD)-responsive endothelial lncRNA. Here we reported that genetic deficiency of Malat1 leads to reduced blood vessel formation and local blood flow perfusion in mouse hind limbs at one to four weeks after hindlimb ischemia. Malat1 and vascular endothelial growth factor receptor 2 (VEGFR2) levels were found to be increased in both cultured mouse primary skeletal muscle microvascular endothelial cells (SMMECs) after 16 h OGD followed by 24 h reperfusion and in mouse gastrocnemius muscle that underwent hindlimb ischemia followed by 28 days of reperfusion. Moreover, Malat1 silencing by locked nucleic acid (LNA)-GapmeRs significantly reduced tube formation, cell migration, and cell proliferation in SMMEC cultures. Mechanistically, RNA subcellular isolation and RNA-immunoprecipitation experiments demonstrate that Malat1 directly targets VEGFR2 to facilitate angiogenesis. The results suggest that Malat1 regulates cell-autonomous angiogenesis through direct regulation of VEGFR2. Full article
Show Figures

Figure 1

11 pages, 2665 KiB  
Article
The Novel miRNA N-72 Regulates EGF-Induced Migration of Human Amnion Mesenchymal Stem Cells by Targeting MMP2
by Ying Li, Dianbao Zhang, Meng Chen, Rui Wang, Tao Zhang, Feng Zhao, Xuewen Lin and Xining Pang
Int. J. Mol. Sci. 2018, 19(5), 1363; https://doi.org/10.3390/ijms19051363 - 04 May 2018
Cited by 4 | Viewed by 4109
Abstract
Human amnion mesenchymal stem cells (hAMSCs) are promising sources of stem cells in regenerative medicine. The migration stimulated by cytokines is critical for mesenchymal stem cells (MSCs)-based cytotherapy, while the regulatory mechanisms of EGF (epidermal growth factor)-induced hAMSC migration are largely unclear. Here, [...] Read more.
Human amnion mesenchymal stem cells (hAMSCs) are promising sources of stem cells in regenerative medicine. The migration stimulated by cytokines is critical for mesenchymal stem cells (MSCs)-based cytotherapy, while the regulatory mechanisms of EGF (epidermal growth factor)-induced hAMSC migration are largely unclear. Here, a novel miRNA N-72 (GenBank accession number: MH269369) has been discovered, and its function on EGF-induced migration in hAMSCs was investigated. High-purity hAMSCs were isolated and cultured in vitro, which were characterized by flow cytometry and trilineage differentiation. The N-72 located on chromosome three was conserved, and pri-N-72 owned the ability to form a stem-loop secondary structure, which was predicated by bioinformatic programs. The expression of mature N-72 was verified in several human cells including hAMSC by real-time PCR. In EGF-stimulated hAMSC, N-72 showed a significant reduction in a PI3K and p38 MAPK-dependent manner, and N-72 mimics transfection-inhibited EGF-induced migration, which was verified by scratch assay and transwell assay. Further, the predicated target gene MMP2 was proved to be a direct target of N-72 via luciferase reporter assay, real-time PCR, and Western blotting. The results that MMP2 silencing repressed hAMSC migration suggested MMP2 as a functional downstream target of N-72. In summary, we have discovered the novel N-72, and it was crucial for EGF-induced migration by targeting MMP2 in hAMSCs. Full article
Show Figures

Figure 1

4 pages, 506 KiB  
Correction
Correction: Sarkar, D., et al. Multiple Isoforms of ANRIL in Melanoma Cells: Structural Complexity Suggests Variations in Processing. Int. J. Mol. Sci. 2017, 18, 1378
by Debina Sarkar, Ali Oghabian, Pasani K. Bodiyabadu, Wayne R. Joseph, Euphemia Y. Leung, Graeme J. Finlay, Bruce C. Baguley and Marjan E. Askarian-Amiri
Int. J. Mol. Sci. 2018, 19(5), 1343; https://doi.org/10.3390/ijms19051343 - 02 May 2018
Cited by 1 | Viewed by 3078 Show Figures

Figure 1

14 pages, 2934 KiB  
Article
Organ-Specific MicroRNAs (MIR122, 137, and 206) Contribute to Tissue Characteristics and Carcinogenesis by Regulating Pyruvate Kinase M1/2 (PKM) Expression
by Kohei Taniguchi, Nobuhiko Sugito, Haruka Shinohara, Yuki Kuranaga, Yosuke Inomata, Kazumasa Komura, Kazuhisa Uchiyama and Yukihiro Akao
Int. J. Mol. Sci. 2018, 19(5), 1276; https://doi.org/10.3390/ijms19051276 - 24 Apr 2018
Cited by 20 | Viewed by 6084
Abstract
Pyruvate kinase is known as the glycolytic enzyme catalyzing the final step in glycolysis. In mammals, two different forms of it exist, i.e., pyruvate kinase M1/2 (PKM) and pyruvate kinase L/R (PKLR). Also, PKM has two isoforms, i.e., PKM1 [...] Read more.
Pyruvate kinase is known as the glycolytic enzyme catalyzing the final step in glycolysis. In mammals, two different forms of it exist, i.e., pyruvate kinase M1/2 (PKM) and pyruvate kinase L/R (PKLR). Also, PKM has two isoforms, i.e., PKM1 and PKM2. These genes have tissue-specific distribution. Namely, PKM1 is distributed in high-energy-demanding organs, such as brain and muscle. Also, PKM2 is distributed in various other organs, such as the colon. On the other hand, PKLR is distributed in liver and red blood cells (RBCs). Interestingly, PKM2 has been recognized as one of the essential genes for the cancer-specific energy metabolism termed the “Warburg effect”. However, the mechanism(s) underlying this fact have remained largely unclear. Recently, we found that some organ-specific microRNAs (miRNAs, MIR) regulate PKM isoform expression through direct targeting of polypyrimidine tract binding protein 1 (PTBP1), which is the splicer responsible for PKM2-dominant expression. In this study, we examined whether this machinery was conserved in the case of other PTBP1- and PKM-targeting miRNAs. We focused on the MIRs 122, 137, and 206, and investigated the expression profiles of each of these miRNAs in tissues from mouse and human organs. Also, we examined the regulatory mechanisms of PKM isoform expression by testing each of these miRNAs in human cancer cell lines. Presently, we found that brain-specific MIR137 and muscle-specific MIR206 predominantly induced PKM1 expression through direct targeting of PTBP1. Also, liver-specific MIR122 suppressed the expression of both PKM1 and PKM2, which action occurred through direct targeting of PKM to enable the expression of PKLR. Moreover, the expression levels of these miRNAs were downregulated in cancer cells that had originated from these tissues, resulting in PKM2 dominance. Our results suggest that the organ-specific distribution of miRNAs is one of the principal means by which miRNA establishes characteristics of a tissue and that dysregulation of these miRNAs results in cancer development through a change in the ratio of PKM isoform expression. Also, our results contribute to cancer diagnosis and will be useful for cancer-specific therapy for the Warburg effect in the near future. Full article
Show Figures

Graphical abstract

15 pages, 7494 KiB  
Article
Hippocampal MicroRNAs Respond to Administration of Antidepressant Fluoxetine in Adult Mice
by Nan Miao, Junghee Jin, Seung-Nam Kim and Tao Sun
Int. J. Mol. Sci. 2018, 19(3), 671; https://doi.org/10.3390/ijms19030671 - 27 Feb 2018
Cited by 15 | Viewed by 6111
Abstract
Current antidepressant treatments to anxiety and depression remain inadequate, burdened by a significant percentage of misuse and drug side-effects, due to unclear mechanisms of actions of antidepressants. To better understand the regulatory roles of antidepressant fluoxetine-related drug reactions, we here investigate changes of [...] Read more.
Current antidepressant treatments to anxiety and depression remain inadequate, burdened by a significant percentage of misuse and drug side-effects, due to unclear mechanisms of actions of antidepressants. To better understand the regulatory roles of antidepressant fluoxetine-related drug reactions, we here investigate changes of expression levels of hippocampal microRNAs (miRNAs) after administration of fluoxetine in normal adult mice. We find that 64 miRNAs showed significant changes between fluoxetine treatment and control groups by analyzing 626 mouse miRNAs. Many miRNAs in response to fluoxetine are involved in neural-related signaling pathways by analyzing miRNA-target gene pairs using the Kyoto encyclopedia of genes and genomes (KEGG) and Gene Ontology (GO). Moreover, miRNAs with altered expression are mainly associated with the repression of the dopaminergic synapse signals, which may affect hippocampal function after fluoxetine treatment. Our results demonstrate that a number of miRNAs respond to antidepressants even in normal mice and may affect target gene expression, which supports the safety consideration of inappropriate treatment and off-label use of antidepressant drugs. Full article
Show Figures

Graphical abstract

23 pages, 1998 KiB  
Review
Plant Responses to Pathogen Attack: Small RNAs in Focus
by Waqar Islam, Ali Noman, Muhammad Qasim and Liande Wang
Int. J. Mol. Sci. 2018, 19(2), 515; https://doi.org/10.3390/ijms19020515 - 08 Feb 2018
Cited by 65 | Viewed by 10891
Abstract
Small RNAs (sRNA) are a significant group of gene expression regulators for multiple biological processes in eukaryotes. In plants, many sRNA silencing pathways produce extensive array of sRNAs with specialized roles. The evidence on record advocates for the functions of sRNAs during plant [...] Read more.
Small RNAs (sRNA) are a significant group of gene expression regulators for multiple biological processes in eukaryotes. In plants, many sRNA silencing pathways produce extensive array of sRNAs with specialized roles. The evidence on record advocates for the functions of sRNAs during plant microbe interactions. Host sRNAs are reckoned as mandatory elements of plant defense. sRNAs involved in plant defense processes via different pathways include both short interfering RNA (siRNA) and microRNA (miRNA) that actively regulate immunity in response to pathogenic attack via tackling pathogen-associated molecular patterns (PAMPs) and other effectors. In response to pathogen attack, plants protect themselves with the help of sRNA-dependent immune systems. That sRNA-mediated plant defense responses play a role during infections is an established fact. However, the regulations of several sRNAs still need extensive research. In this review, we discussed the topical advancements and findings relevant to pathogen attack and plant defense mediated by sRNAs. We attempted to point out diverse sRNAs as key defenders in plant systems. It is hoped that sRNAs would be exploited as a mainstream player to achieve food security by tackling different plant diseases. Full article
Show Figures

Figure 1

15 pages, 665 KiB  
Review
Regulatory Role of MicroRNAs in Muscle Atrophy during Exercise Intervention
by Shufang Zhang and Ning Chen
Int. J. Mol. Sci. 2018, 19(2), 405; https://doi.org/10.3390/ijms19020405 - 30 Jan 2018
Cited by 29 | Viewed by 8295
Abstract
Skeletal muscle comprising approximately 40% of body weight is highly important for locomotion and metabolic homeostasis. The growth and regeneration of skeletal muscle are highly organized processes; thus, it is not surprising to reveal certain complexity during these regulatory processes. Recently, a large [...] Read more.
Skeletal muscle comprising approximately 40% of body weight is highly important for locomotion and metabolic homeostasis. The growth and regeneration of skeletal muscle are highly organized processes; thus, it is not surprising to reveal certain complexity during these regulatory processes. Recently, a large number of evidence indicate that microRNAs can result in obvious impacts on growth, regeneration and metabolism of skeletal muscle. In this review, recent research achievements of microRNAs in regulating myogenesis, atrophy and aging during exercise intervention are discussed, which will provide the guidance for developing potential applications of microRNAs in health promotion and rehabilitation of sports injuries. Full article
Show Figures

Graphical abstract

23 pages, 1957 KiB  
Review
Natural Antisense Transcripts: Molecular Mechanisms and Implications in Breast Cancers
by Guillaume Latgé, Christophe Poulet, Vincent Bours, Claire Josse and Guy Jerusalem
Int. J. Mol. Sci. 2018, 19(1), 123; https://doi.org/10.3390/ijms19010123 - 02 Jan 2018
Cited by 57 | Viewed by 7266
Abstract
Natural antisense transcripts are RNA sequences that can be transcribed from both DNA strands at the same locus but in the opposite direction from the gene transcript. Because strand-specific high-throughput sequencing of the antisense transcriptome has only been available for less than a [...] Read more.
Natural antisense transcripts are RNA sequences that can be transcribed from both DNA strands at the same locus but in the opposite direction from the gene transcript. Because strand-specific high-throughput sequencing of the antisense transcriptome has only been available for less than a decade, many natural antisense transcripts were first described as long non-coding RNAs. Although the precise biological roles of natural antisense transcripts are not known yet, an increasing number of studies report their implication in gene expression regulation. Their expression levels are altered in many physiological and pathological conditions, including breast cancers. Among the potential clinical utilities of the natural antisense transcripts, the non-coding|coding transcript pairs are of high interest for treatment. Indeed, these pairs can be targeted by antisense oligonucleotides to specifically tune the expression of the coding-gene. Here, we describe the current knowledge about natural antisense transcripts, their varying molecular mechanisms as gene expression regulators, and their potential as prognostic or predictive biomarkers in breast cancers. Full article
Show Figures

Graphical abstract

2017

Jump to: 2023, 2022, 2021, 2020, 2019, 2018, 2016, 2015, 2014

1991 KiB  
Article
Integrated MicroRNA–mRNA Analysis Reveals miR-204 Inhibits Cell Proliferation in Gastric Cancer by Targeting CKS1B, CXCL1 and GPRC5A
by Sirjana Shrestha, Chi-Dung Yang, Hsiao-Chin Hong, Chih-Hung Chou, Chun-San Tai, Men-Yee Chiew, Wen-Liang Chen, Shun-Long Weng, Chung-Chu Chen, Yi-An Chang, Meng-Lin Lee, Wei-Yun Huang, Sheng-Da Hsu, Yi-Chang Chen and Hsien-Da Huang
Int. J. Mol. Sci. 2018, 19(1), 87; https://doi.org/10.3390/ijms19010087 - 28 Dec 2017
Cited by 34 | Viewed by 6709
Abstract
Gastric cancer (GC) is the second most frequent cause of cancer-related deaths worldwide. MicroRNAs are single-stranded RNA molecules of 21–23 nucleotides that regulate target gene expression through specific base-pairing interactions between miRNA and untranslated regions of targeted mRNAs. In this study, we generated [...] Read more.
Gastric cancer (GC) is the second most frequent cause of cancer-related deaths worldwide. MicroRNAs are single-stranded RNA molecules of 21–23 nucleotides that regulate target gene expression through specific base-pairing interactions between miRNA and untranslated regions of targeted mRNAs. In this study, we generated a multistep approach for the integrated analysis of miRNA and mRNA expression. First, both miRNA and mRNA expression profiling datasets in gastric cancer from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) identified 79 and 1042 differentially expressed miRNAs and mRNAs, respectively, in gastric cancer. Second, inverse correlations between miRNA and mRNA expression levels identified 3206 miRNA–mRNA pairs combined with 79 dysregulated miRNAs and their 774 target mRNAs predicted by three prediction tools, miRanda, PITA, and RNAhybrid. Additionally, miR-204, which was found to be down-regulated in gastric cancer, was ectopically over-expressed in the AGS gastric cancer cell line and all down-regulated targets were identified by RNA sequencing (RNA-seq) analysis. Over-expression of miR-204 reduced the gastric cancer cell proliferation and suppressed the expression of three targets which were validated by qRT-PCR and luciferase assays. For the first time, we identified that CKS1B, CXCL1, and GPRC5A are putative targets of miR-204 and elucidated that miR-204 acted as potential tumor suppressor and, therefore, are useful as a promising therapeutic target for gastric cancer. Full article
Show Figures

Figure 1

1011 KiB  
Review
microRNAs in Parkinson’s Disease: From Pathogenesis to Novel Diagnostic and Therapeutic Approaches
by Loredana Leggio, Silvia Vivarelli, Francesca L’Episcopo, Cataldo Tirolo, Salvo Caniglia, Nunzio Testa, Bianca Marchetti and Nunzio Iraci
Int. J. Mol. Sci. 2017, 18(12), 2698; https://doi.org/10.3390/ijms18122698 - 13 Dec 2017
Cited by 158 | Viewed by 10121
Abstract
Parkinson’s disease (PD) is the most prevalent central nervous system (CNS) movement disorder and the second most common neurodegenerative disease overall. PD is characterized by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) within the midbrain, accumulation [...] Read more.
Parkinson’s disease (PD) is the most prevalent central nervous system (CNS) movement disorder and the second most common neurodegenerative disease overall. PD is characterized by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) within the midbrain, accumulation of alpha-synuclein (α-SYN) in Lewy bodies and neurites and excessive neuroinflammation. The neurodegenerative processes typically begin decades before the appearance of clinical symptoms. Therefore, the diagnosis is achievable only when the majority of the relevant DAergic neurons have already died and for that reason available treatments are only palliative at best. The causes and mechanism(s) of this devastating disease are ill-defined but complex interactions between genetic susceptibility and environmental factors are considered major contributors to the etiology of PD. In addition to the role of classical gene mutations in PD, the importance of regulatory elements modulating gene expression has been increasingly recognized. One example is the critical role played by microRNAs (miRNAs) in the development and homeostasis of distinct populations of neurons within the CNS and, in particular, in the context of PD. Recent reports demonstrate how distinct miRNAs are involved in the regulation of PD genes, whereas profiling approaches are unveiling variations in the abundance of certain miRNAs possibly relevant either to the onset or to the progression of the disease. In this review, we provide an overview of the miRNAs recently found to be implicated in PD etiology, with particular focus on their potential relevance as PD biomarkers, as well as their possible use in PD targeted therapy. Full article
Show Figures

Graphical abstract

707 KiB  
Review
Long Non-Coding RNAs in Metabolic Organs and Energy Homeostasis
by Maude Giroud and Marcel Scheideler
Int. J. Mol. Sci. 2017, 18(12), 2578; https://doi.org/10.3390/ijms18122578 - 30 Nov 2017
Cited by 55 | Viewed by 8271
Abstract
Single cell organisms can surprisingly exceed the number of human protein-coding genes, which are thus not at the origin of the complexity of an organism. In contrast, the relative amount of non-protein-coding sequences increases consistently with organismal complexity. Moreover, the mammalian transcriptome predominantly [...] Read more.
Single cell organisms can surprisingly exceed the number of human protein-coding genes, which are thus not at the origin of the complexity of an organism. In contrast, the relative amount of non-protein-coding sequences increases consistently with organismal complexity. Moreover, the mammalian transcriptome predominantly comprises non-(protein)-coding RNAs (ncRNA), of which the long ncRNAs (lncRNAs) constitute the most abundant part. lncRNAs are highly species- and tissue-specific with very versatile modes of action in accordance with their binding to a large spectrum of molecules and their diverse localization. lncRNAs are transcriptional regulators adding an additional regulatory layer in biological processes and pathophysiological conditions. Here, we review lncRNAs affecting metabolic organs with a focus on the liver, pancreas, skeletal muscle, cardiac muscle, brain, and adipose organ. In addition, we will discuss the impact of lncRNAs on metabolic diseases such as obesity and diabetes. In contrast to the substantial number of lncRNA loci in the human genome, the functionally characterized lncRNAs are just the tip of the iceberg. So far, our knowledge concerning lncRNAs in energy homeostasis is still in its infancy, meaning that the rest of the iceberg is a treasure chest yet to be discovered. Full article
Show Figures

Graphical abstract

3788 KiB  
Article
BCL11A mRNA Targeting by miR-210: A Possible Network Regulating γ-Globin Gene Expression
by Jessica Gasparello, Enrica Fabbri, Nicoletta Bianchi, Giulia Breveglieri, Cristina Zuccato, Monica Borgatti, Roberto Gambari and Alessia Finotti
Int. J. Mol. Sci. 2017, 18(12), 2530; https://doi.org/10.3390/ijms18122530 - 26 Nov 2017
Cited by 35 | Viewed by 6073
Abstract
The involvement of microRNAs in the control of repressors of human γ-globin gene transcription has been firmly demonstrated, as described for the miR-486-3p mediated down-regulation of BCL11A. On the other hand, we have reported that miR-210 is involved in erythroid differentiation and, possibly, [...] Read more.
The involvement of microRNAs in the control of repressors of human γ-globin gene transcription has been firmly demonstrated, as described for the miR-486-3p mediated down-regulation of BCL11A. On the other hand, we have reported that miR-210 is involved in erythroid differentiation and, possibly, in γ-globin gene up-regulation. In the present study, we have identified the coding sequence of BCL11A as a possible target of miR-210. The following results sustain this hypothesis: (a) interactions between miR-210 and the miR-210 BCL11A site were demonstrated by SPR-based biomolecular interaction analysis (BIA); (b) the miR-210 site of BCL11A is conserved through molecular evolution; (c) forced expression of miR-210 leads to decrease of BCL11A-XL and increase of γ-globin mRNA content in erythroid cells, including erythroid precursors isolated from β-thalassemia patients. Our study suggests that the coding mRNA sequence of BCL11A can be targeted by miR-210. In addition to the theoretical point of view, these data are of interest from the applied point of view, supporting a novel strategy to inhibit BCL11A by mimicking miR-210 functions, accordingly with the concept supported by several papers and patent applications that inhibition of BCL11A is an efficient strategy for fetal hemoglobin induction in the treatment of β-thalassemia. Full article
Show Figures

Figure 1

1286 KiB  
Review
Long Non-Coding RNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Regulation, Functions, and Underlying Mechanisms
by Lipeng Qiu, Tao Wang, Xiuquan Xu, Yihang Wu, Qi Tang and Keping Chen
Int. J. Mol. Sci. 2017, 18(12), 2505; https://doi.org/10.3390/ijms18122505 - 23 Nov 2017
Cited by 31 | Viewed by 6363
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death in the world. Hepatitis B virus (HBV) and its X gene-encoded protein (HBx) play important roles in the progression of HCC. Although long non-coding RNAs (lncRNAs) [...] Read more.
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death in the world. Hepatitis B virus (HBV) and its X gene-encoded protein (HBx) play important roles in the progression of HCC. Although long non-coding RNAs (lncRNAs) cannot encode proteins, growing evidence indicates that they play essential roles in HCC progression, and contribute to cell proliferation, invasion and metastasis, autophagy, and apoptosis by targeting a large number of pivotal protein-coding genes, miRNAs, and signaling pathways. In this review, we briefly outline recent findings of differentially expressed lncRNAs in HBV-related HCC, with particular focus on several key lncRNAs, and discuss their regulation by HBV/HBx, their functions, and their underlying molecular mechanisms in the progression of HCC. Full article
Show Figures

Graphical abstract

780 KiB  
Review
MicroRNAs Associated with Von Hippel–Lindau Pathway in Renal Cell Carcinoma: A Comprehensive Review
by Lisa-Maria Schanza, Maximilian Seles, Michael Stotz, Johannes Fosselteder, Georg C. Hutterer, Martin Pichler and Verena Stiegelbauer
Int. J. Mol. Sci. 2017, 18(11), 2495; https://doi.org/10.3390/ijms18112495 - 22 Nov 2017
Cited by 39 | Viewed by 7376
Abstract
Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the [...] Read more.
Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired resistance towards therapeutic agents over time. The discovery of microRNAs (miRNAs), a class of small, non-coding, single-stranded RNAs that play a crucial role in post-transcriptional regulation, has added new dimensions to the development of novel diagnostic and treatment tools. Because of an association between Von Hippel–Lindau (VHL) genes with chromosomal loss in 3p25-26 and clear cell RCC, miRNAs have attracted considerable scientific interest over the last years. The loss of VHL function leads to constitutional activation of the hypoxia inducible factor (HIF) pathway and to consequent expression of numerous angiogenic and carcinogenic factors. Since miRNAs represent key players of carcinogenesis, tumor cell invasion, angiogenesis, as well as in development of metastases in RCC, they might serve as potential therapeutic targets. Several miRNAs are already known to be dysregulated in RCC and have been linked to biological processes involved in tumor angiogenesis and response to anti-cancer therapies. This review summarizes the role of different miRNAs in RCC angiogenesis and their association with the VHL gene, highlighting their potential role as novel drug targets. Full article
Show Figures

Graphical abstract

1148 KiB  
Review
The Dark Side of the Epitranscriptome: Chemical Modifications in Long Non-Coding RNAs
by Roland Jacob, Sindy Zander and Tony Gutschner
Int. J. Mol. Sci. 2017, 18(11), 2387; https://doi.org/10.3390/ijms18112387 - 10 Nov 2017
Cited by 86 | Viewed by 8524
Abstract
The broad application of next-generation sequencing technologies in conjunction with improved bioinformatics has helped to illuminate the complexity of the transcriptome, both in terms of quantity and variety. In humans, 70–90% of the genome is transcribed, but only ~2% carries the blueprint for [...] Read more.
The broad application of next-generation sequencing technologies in conjunction with improved bioinformatics has helped to illuminate the complexity of the transcriptome, both in terms of quantity and variety. In humans, 70–90% of the genome is transcribed, but only ~2% carries the blueprint for proteins. Hence, there is a huge class of non-translated transcripts, called long non-coding RNAs (lncRNAs), which have received much attention in the past decade. Several studies have shown that lncRNAs are involved in a plethora of cellular signaling pathways and actively regulate gene expression via a broad selection of molecular mechanisms. Only recently, sequencing-based, transcriptome-wide studies have characterized different types of post-transcriptional chemical modifications of RNAs. These modifications have been shown to affect the fate of RNA and further expand the variety of the transcriptome. However, our understanding of their biological function, especially in the context of lncRNAs, is still in its infancy. In this review, we will focus on three epitranscriptomic marks, namely pseudouridine (Ψ), N6-methyladenosine (m6A) and 5-methylcytosine (m5C). We will introduce writers, readers, and erasers of these modifications, and we will present methods for their detection. Finally, we will provide insights into the distribution and function of these chemical modifications in selected, cancer-related lncRNAs. Full article
Show Figures

Figure 1

1798 KiB  
Article
Magnetic Beads-Based Sensor with Tailored Sensitivity for Rapid and Single-Step Amperometric Determination of miRNAs
by Eva Vargas, Rebeca M. Torrente-Rodríguez, Víctor Ruiz-Valdepeñas Montiel, Eloy Povedano, María Pedrero, Juan J. Montoya, Susana Campuzano and José M. Pingarrón
Int. J. Mol. Sci. 2017, 18(11), 2151; https://doi.org/10.3390/ijms18112151 - 09 Nov 2017
Cited by 29 | Viewed by 9225
Abstract
This work describes a sensitive amperometric magneto-biosensor for single-step and rapid determination of microRNAs (miRNAs). The developed strategy involves the use of direct hybridization of the target miRNA (miRNA-21) with a specific biotinylated DNA probe immobilized on streptavidin-modified magnetic beads (MBs), and labeling [...] Read more.
This work describes a sensitive amperometric magneto-biosensor for single-step and rapid determination of microRNAs (miRNAs). The developed strategy involves the use of direct hybridization of the target miRNA (miRNA-21) with a specific biotinylated DNA probe immobilized on streptavidin-modified magnetic beads (MBs), and labeling of the resulting heteroduplexes with a specific DNA–RNA antibody and the bacterial protein A (ProtA) conjugated with an horseradish peroxidase (HRP) homopolymer (Poly-HRP40) as an enzymatic label for signal amplification. Amperometric detection is performed upon magnetic capture of the modified MBs onto the working electrode surface of disposable screen-printed carbon electrodes (SPCEs) using the H2O2/hydroquinone (HQ) system. The magnitude of the cathodic signal obtained at −0.20 V (vs. the Ag pseudo-reference electrode) demonstrated linear dependence with the concentration of the synthetic target miRNA over the 1.0 to 100 pM range. The method provided a detection limit (LOD) of 10 attomoles (in a 25 μL sample) without any target miRNA amplification in just 30 min (once the DNA capture probe-MBs were prepared). This approach shows improved sensitivity compared with that of biosensors constructed with the same anti-DNA–RNA Ab as capture instead of a detector antibody and further labeling with a Strep-HRP conjugate instead of the Poly-HRP40 homopolymer. The developed strategy involves a single step working protocol, as well as the possibility to tailor the sensitivity by enlarging the length of the DNA/miRNA heteroduplexes using additional probes and/or performing the labelling with ProtA conjugated with homopolymers prepared with different numbers of HRP molecules. The practical usefulness was demonstrated by determination of the endogenous levels of the mature target miRNA in 250 ng raw total RNA (RNAt) extracted from human mammary epithelial normal (MCF-10A) and cancer (MCF-7) cells and tumor tissues. Full article
Show Figures

Graphical abstract

1039 KiB  
Review
miRNAs, Melanoma and Microenvironment: An Intricate Network
by Gabriele Romano and Lawrence N. Kwong
Int. J. Mol. Sci. 2017, 18(11), 2354; https://doi.org/10.3390/ijms18112354 - 07 Nov 2017
Cited by 43 | Viewed by 9278
Abstract
miRNAs are central players in cancer biology and they play a pivotal role in mediating the network communication between tumor cells and their microenvironment. In melanoma, miRNAs can impair or facilitate a wide array of processes, and here we will focus on: the [...] Read more.
miRNAs are central players in cancer biology and they play a pivotal role in mediating the network communication between tumor cells and their microenvironment. In melanoma, miRNAs can impair or facilitate a wide array of processes, and here we will focus on: the epithelial to mesenchymal transition (EMT), the immune milieu, and metabolism. Multiple miRNAs can affect the EMT process, even at a distance, for example through exosome-mediated mechanisms. miRNAs also strongly act on some components of the immune system, regulating the activity of key elements such as antigen presenting cells, and can facilitate an immune evasive/suppressive phenotype. miRNAs are also involved in the regulation of metabolic processes, specifically in response to hypoxic stimuli where they can mediate the metabolic switch from an oxidative to a glycolytic metabolism. Overall, this review discusses and summarizes recent findings on miRNA regulation in the melanoma tumor microenvironment, analyzing their potential diagnostic and therapeutic applications. Full article
Show Figures

Figure 1

1465 KiB  
Review
Regulation of Human Breast Cancer by the Long Non-Coding RNA H19
by Jordan Collette, Xuefen Le Bourhis and Eric Adriaenssens
Int. J. Mol. Sci. 2017, 18(11), 2319; https://doi.org/10.3390/ijms18112319 - 03 Nov 2017
Cited by 78 | Viewed by 9247
Abstract
Breast cancer is one of the most common causes of cancer related deaths in women. Despite the progress in early detection and use of new therapeutic targets associated with development of novel therapeutic options, breast cancer remains a major problem in public health. [...] Read more.
Breast cancer is one of the most common causes of cancer related deaths in women. Despite the progress in early detection and use of new therapeutic targets associated with development of novel therapeutic options, breast cancer remains a major problem in public health. Indeed, even if the survival rate has improved for breast cancer patients, the number of recurrences within five years and the five-year relative survival rate in patients with metastasis remain dramatic. Thus, the discovery of new molecular actors involved in breast progression is essential to improve the management of this disease. Numerous data indicate that long non-coding RNA are implicated in breast cancer development. The oncofetal lncRNA H19 was the first RNA identified as a riboregulator. Studying of this lncRNA revealed its implication in both normal development and diseases. In this review, we summarize the different mechanisms of action of H19 in human breast cancer. Full article
Show Figures

Figure 1

857 KiB  
Review
To Wnt or Lose: The Missing Non-Coding Linc in Colorectal Cancer
by Peng Shen, Martin Pichler, Meng Chen, George A. Calin and Hui Ling
Int. J. Mol. Sci. 2017, 18(9), 2003; https://doi.org/10.3390/ijms18092003 - 20 Sep 2017
Cited by 44 | Viewed by 8472
Abstract
Colorectal cancer (CRC) is the third most frequent cancer and one of the leading causes for cancer-related mortality. Aberrant activation of the Wnt signaling is an essential initiating factor in colon carcinogenesis, and a driving force of CRC progression. Recently, long non-coding RNAs [...] Read more.
Colorectal cancer (CRC) is the third most frequent cancer and one of the leading causes for cancer-related mortality. Aberrant activation of the Wnt signaling is an essential initiating factor in colon carcinogenesis, and a driving force of CRC progression. Recently, long non-coding RNAs (lncRNAs) have emerged as significant players in CRC pathogenesis through diversified mechanisms. Although both Wnt signaling and lncRNAs represent interesting research areas for CRC, an effort of directly connecting these two areas is lacking. To fill in the knowledge gap, we focus on the reported findings of lncRNAs that regulate Wnt signaling or essential Wnt signaling targets. These include several newly discovered lncRNAs originated from the amplified cancer-associated chromosome 8q24 region that surrounds the essential Wnt target MYC gene, lncRNAs reported to be involved in CRC stem cells, and several individual lncRNAs connected to Wnt signaling through other mechanisms. This review will provide essential information that assists in understanding the missing link of lncRNAs to the classical Wnt signaling in CRC. Full article
Show Figures

Figure 1

1119 KiB  
Review
MicroRNAs in Different Histologies of Soft Tissue Sarcoma: A Comprehensive Review
by Maria Anna Smolle, Andreas Leithner, Florian Posch, Joanna Szkandera, Bernadette Liegl-Atzwanger and Martin Pichler
Int. J. Mol. Sci. 2017, 18(9), 1960; https://doi.org/10.3390/ijms18091960 - 12 Sep 2017
Cited by 39 | Viewed by 5353
Abstract
Soft tissue sarcomas (STS) constitute a rare tumour entity comprising over 50 histological subtypes. MicroRNAs (miRNAs) are short non-protein coding RNA molecules that regulate gene expression by targeting the 3’-untranslated region of messenger RNAs. They are involved in a variety of human diseases, [...] Read more.
Soft tissue sarcomas (STS) constitute a rare tumour entity comprising over 50 histological subtypes. MicroRNAs (miRNAs) are short non-protein coding RNA molecules that regulate gene expression by targeting the 3’-untranslated region of messenger RNAs. They are involved in a variety of human diseases, including malignancies, such as endometrial cancer, osteosarcoma, bronchial carcinoma and breast cancer. In STS, various miRNAs are differentially expressed, thus contributing to development, progression and invasion. Therefore, the aim of the present review is to summarise current knowledge on the role of miRNAs in STS. Furthermore, the potential role of miRNAs as diagnostic, prognostic and predictive biomarkers is discussed. Full article
Show Figures

Graphical abstract

17895 KiB  
Article
MiR-30a-5p Inhibits Epithelial-to-Mesenchymal Transition and Upregulates Expression of Tight Junction Protein Claudin-5 in Human Upper Tract Urothelial Carcinoma Cells
by Yueh-Hua Chung, Sung-Chou Li, Ying-Hsien Kao, Hao-Lun Luo, Yuan-Tso Cheng, Pey-Ru Lin, Ming-Hong Tai and Po-Hui Chiang
Int. J. Mol. Sci. 2017, 18(8), 1826; https://doi.org/10.3390/ijms18081826 - 22 Aug 2017
Cited by 29 | Viewed by 5220
Abstract
The involvement of microRNAs (miRNAs) in cancer development and their potential as prognostic biomarkers are becoming increasingly known. However, the signature of miRNAs and their regulatory roles in tumorigenesis of upper tract urothelial carcinoma (UTUC) remain to be elucidated. This study aimed to [...] Read more.
The involvement of microRNAs (miRNAs) in cancer development and their potential as prognostic biomarkers are becoming increasingly known. However, the signature of miRNAs and their regulatory roles in tumorigenesis of upper tract urothelial carcinoma (UTUC) remain to be elucidated. This study aimed to profile the miRNA expression pattern in UTUC tumor tissues and identify candidate miRNAs with prognostic and/or therapeutic functions. Methods and Results: We collected 22 UTUC tissue and adjacent normal tissues samples from patients who underwent nephroureterectomy. The miRNAs signatures of three selected UTUC samples using next-generation sequencing showed that miR-30a-5p was significantly downregulated in UTUC tumors compared to adjacent normal tissues. The differentially-expressed miRNAs were specifically validated by quantitative real-time polymerase chain reaction. In addition, the miRNA expression signatures were analyzed with the transcriptome profile characterized by microarray. Further in vitro studies indicated that overexpression of miR-30a-5p significantly suppressed proliferation, migration, and epithelial-to-mesenchymal transition (EMT) in cultured BFTC-909 UTUC cells. As a potential target gene of miR-30a-5p in the tight junction pathway suggested by the pathway enrichment analysis, the reduced expression of tight junction protein claudin-5 in UTUC cells was demonstrated to be upregulated by miR-30a-5p genetic delivery. Conclusions: Taken together, our findings demonstrated that miR-30a-5p inhibits proliferation, metastasis, and EMT, and upregulates the expression of tight junction claudin-5 in UTUC cells. Thus, miR-30a-5p may provide a promising therapeutic strategy for UTUC treatment. Full article
Show Figures

Graphical abstract

970 KiB  
Article
Differential miR-346 and miR-582-3p Expression in Association with Selected Maternal and Fetal Complications
by Pei-Yin Tsai, Sheng-Hsiang Li, Wan-Ni Chen, Hui-Ling Tsai and Mei-Tsz Su
Int. J. Mol. Sci. 2017, 18(7), 1570; https://doi.org/10.3390/ijms18071570 - 19 Jul 2017
Cited by 22 | Viewed by 4070
Abstract
Several miRNAs are expressed in human gestational tissue, and some have been shown to be associated with placental dysfunction and complicated pregnancy outcomes. To investigate the roles of miR-346 and miR-582-3p in adverse obstetric events, we analyzed these 2 miRNAs in three samples [...] Read more.
Several miRNAs are expressed in human gestational tissue, and some have been shown to be associated with placental dysfunction and complicated pregnancy outcomes. To investigate the roles of miR-346 and miR-582-3p in adverse obstetric events, we analyzed these 2 miRNAs in three samples (maternal blood, umbilical cord blood and placenta) obtained from pregnant women in four groups, including healthy control (n = 60), preeclampsia (n = 31), preterm delivery (n = 29) and small for gestational age (n = 19) patients. The expression levels of miR-346 and miR-582-3p in all included adverse obstetric outcome groups were significantly higher in the maternal plasma samples but lower in the placenta samples (all p value < 0.05). In addition, the miR-346 expression levels in fetal cord blood were also significantly lower in all of the included adverse obstetric outcome groups (all p < 0.05). Multivariate analysis of the three specimens after adjusting for maternal age and gestational age at delivery gave the same results. In conclusion, aberrant miR-346 and miR-582-3p expression level in pregnancy was associated with multiple maternal and fetal complications. Their differential expression in maternal blood, umbilical cord blood and placenta could be potential biomarkers or therapeutic targets for adverse obstetric outcomes Full article
Show Figures

Graphical abstract

3861 KiB  
Article
Induction of miR-3648 Upon ER Stress and Its Regulatory Role in Cell Proliferation
by Farooq Rashid, Hassaan Mehboob Awan, Abdullah Shah, Liang Chen and Ge Shan
Int. J. Mol. Sci. 2017, 18(7), 1375; https://doi.org/10.3390/ijms18071375 - 29 Jun 2017
Cited by 25 | Viewed by 5135
Abstract
MicroRNAs (miRNAs) play important roles under multiple cellular conditions including endoplasmic reticulum (ER) stress. We found that miR-3648, a human specific microRNA, was induced under ER stress. Moreover, Adenomatous polyposis coli 2 (APC2), a tumor suppressor and a negative regulator of Wnt signaling, [...] Read more.
MicroRNAs (miRNAs) play important roles under multiple cellular conditions including endoplasmic reticulum (ER) stress. We found that miR-3648, a human specific microRNA, was induced under ER stress. Moreover, Adenomatous polyposis coli 2 (APC2), a tumor suppressor and a negative regulator of Wnt signaling, was found to be the direct target of miR-3648. Levels of APC2 were downregulated when cells were under ER stress or after overexpressing miR-3648. Inhibition of miR-3648 by antagomir increased APC2 levels and decreased cell proliferation. Conversely, when miR-3648 was overexpressed, APC2 levels were decreased and the cell growth increased. Our data demonstrated that ER stress mediated induction of miR-3648 in human cells, which then downregulated APC2 to increase cell proliferation. Full article
Show Figures

Graphical abstract

1186 KiB  
Article
Multiple Isoforms of ANRIL in Melanoma Cells: Structural Complexity Suggests Variations in Processing
by Debina Sarkar, Ali Oghabian, Pasani K. Bodiyabadu, Wayne R. Joseph, Euphemia Y. Leung, Graeme J. Finlay, Bruce C. Baguley and Marjan E. Askarian-Amiri
Int. J. Mol. Sci. 2017, 18(7), 1378; https://doi.org/10.3390/ijms18071378 - 27 Jun 2017
Cited by 31 | Viewed by 5767 | Correction
Abstract
The long non-coding RNA ANRIL, antisense to the CDKN2B locus, is transcribed from a gene that encompasses multiple disease-associated polymorphisms. Despite the identification of multiple isoforms of ANRIL, expression of certain transcripts has been found to be tissue-specific and the characterisation [...] Read more.
The long non-coding RNA ANRIL, antisense to the CDKN2B locus, is transcribed from a gene that encompasses multiple disease-associated polymorphisms. Despite the identification of multiple isoforms of ANRIL, expression of certain transcripts has been found to be tissue-specific and the characterisation of ANRIL transcripts remains incomplete. Several functions have been associated with ANRIL. In our judgement, studies on ANRIL functionality are premature pending a more complete appreciation of the profusion of isoforms. We found differential expression of ANRIL exons, which indicates that multiple isoforms exist in melanoma cells. In addition to linear isoforms, we identified circular forms of ANRIL (circANRIL). Further characterisation of circANRIL in two patient-derived metastatic melanoma cell lines (NZM7 and NZM37) revealed the existence of a rich assortment of circular isoforms. Moreover, in the two melanoma cell lines investigated, the complements of circANRIL isoforms were almost completely different. Novel exons were also discovered. We also found the family of linear ANRIL was enriched in the nucleus, whilst the circular isoforms were enriched in the cytoplasm and they differed markedly in stability. With respect to the variable processing of circANRIL species, bioinformatic analysis indicated that intronic Arthrobacter luteus (Alu) restriction endonuclease inverted repeats and exon skipping were not involved in selection of back-spliced exon junctions. Based on our findings, we hypothesise that “ANRIL” has wholly distinct dual sets of functions in melanoma. This reveals the dynamic nature of the locus and constitutes a basis for investigating the functions of ANRIL in melanoma. Full article
Show Figures

Graphical abstract

923 KiB  
Review
Mechanistic Insight into Long Noncoding RNAs and the Placenta
by Dale McAninch, Claire T. Roberts and Tina Bianco-Miotto
Int. J. Mol. Sci. 2017, 18(7), 1371; https://doi.org/10.3390/ijms18071371 - 27 Jun 2017
Cited by 53 | Viewed by 6416
Abstract
Long non-coding RNAs (lncRNAs) are classified as RNAs greater than 200 nucleotides in length that do not produce a protein product. lncRNAs are expressed with cellular and temporal specificity and have been shown to play a role in many cellular events, including the [...] Read more.
Long non-coding RNAs (lncRNAs) are classified as RNAs greater than 200 nucleotides in length that do not produce a protein product. lncRNAs are expressed with cellular and temporal specificity and have been shown to play a role in many cellular events, including the regulation of gene expression, post-transcriptional modifications and epigenetic modifications. Since lncRNAs were first discovered, there has been increasing evidence that they play important roles in the development and function of most organs, including the placenta. The placenta is an essential transient organ that facilitates communication and nutrient exchange between the mother and foetus. The placenta is of foetal origin and begins to form shortly after the embryo implants into the uterine wall. The placenta relies heavily on the successful differentiation and function of trophoblast cells, including invasion as well as the formation of the maternal/foetal interface. Here, we review the current literature surrounding the involvement of lncRNAs in the development and function of trophoblasts and the human placenta. Full article
Show Figures

Graphical abstract

863 KiB  
Review
Micro-RNAs as Potential Predictors of Response to Breast Cancer Systemic Therapy: Future Clinical Implications
by Alma D. Campos-Parra, Gerardo Cuamani Mitznahuatl, Abraham Pedroza-Torres, Rafael Vázquez Romo, Fany Iris Porras Reyes, Eduardo López-Urrutia and Carlos Pérez-Plasencia
Int. J. Mol. Sci. 2017, 18(6), 1182; https://doi.org/10.3390/ijms18061182 - 02 Jun 2017
Cited by 40 | Viewed by 6257
Abstract
Despite advances in diagnosis and new treatments such as targeted therapies, breast cancer (BC) is still the most prevalent tumor in women worldwide and the leading cause of death. The principal obstacle for successful BC treatment is the acquired or de novo resistance [...] Read more.
Despite advances in diagnosis and new treatments such as targeted therapies, breast cancer (BC) is still the most prevalent tumor in women worldwide and the leading cause of death. The principal obstacle for successful BC treatment is the acquired or de novo resistance of the tumors to the systemic therapy (chemotherapy, endocrine, and targeted therapies) that patients receive. In the era of personalized treatment, several studies have focused on the search for biomarkers capable of predicting the response to this therapy; microRNAs (miRNAs) stand out among these markers due to their broad spectrum or potential clinical applications. miRNAs are conserved small non-coding RNAs that act as negative regulators of gene expression playing an important role in several cellular processes, such as cell proliferation, autophagy, genomic stability, and apoptosis. We reviewed recent data that describe the role of miRNAs as potential predictors of response to systemic treatments in BC. Furthermore, upon analyzing the collected published information, we noticed that the overexpression of miR-155, miR-222, miR-125b, and miR-21 predicts the resistance to the most common systemic treatments; nonetheless, the function of these particular miRNAs must be carefully studied and further analyses are still necessary to increase knowledge about their role and future potential clinical uses in BC. Full article
Show Figures

Graphical abstract

2360 KiB  
Review
Dietary Intervention by Phytochemicals and Their Role in Modulating Coding and Non-Coding Genes in Cancer
by Liviuta Budisan, Diana Gulei, Oana Mihaela Zanoaga, Alexandra Iulia Irimie, Sergiu Chira, Cornelia Braicu, Claudia Diana Gherman and Ioana Berindan-Neagoe
Int. J. Mol. Sci. 2017, 18(6), 1178; https://doi.org/10.3390/ijms18061178 - 01 Jun 2017
Cited by 80 | Viewed by 8348
Abstract
Phytochemicals are natural compounds synthesized as secondary metabolites in plants, representing an important source of molecules with a wide range of therapeutic applications. These natural agents are important regulators of key pathological processes/conditions, including cancer, as they are able to modulate the expression [...] Read more.
Phytochemicals are natural compounds synthesized as secondary metabolites in plants, representing an important source of molecules with a wide range of therapeutic applications. These natural agents are important regulators of key pathological processes/conditions, including cancer, as they are able to modulate the expression of coding and non-coding transcripts with an oncogenic or tumour suppressor role. These natural agents are currently exploited for the development of therapeutic strategies alone or in tandem with conventional treatments for cancer. The aim of this paper is to review the recent studies regarding the role of these natural phytochemicals in different processes related to cancer inhibition, including apoptosis activation, angiogenesis and metastasis suppression. From the large palette of phytochemicals we selected epigallocatechin gallate (EGCG), caffeic acid phenethyl ester (CAPE), genistein, morin and kaempferol, due to their increased activity in modulating multiple coding and non-coding genes, targeting the main hallmarks of cancer. Full article
Show Figures

Graphical abstract

3136 KiB  
Article
Loss of BAX by miR-365 Promotes Cutaneous Squamous Cell Carcinoma Progression by Suppressing Apoptosis
by Liang Zhou, Ruirui Gao, Yinghui Wang, Meijuan Zhou and Zhenhua Ding
Int. J. Mol. Sci. 2017, 18(6), 1157; https://doi.org/10.3390/ijms18061157 - 30 May 2017
Cited by 26 | Viewed by 4799
Abstract
Pro-apoptotic BCL2 associated X (BAX) is traditionally thought to be regulated by anti-apoptotic BCL-2 family members, like BCL2-like 1 (BCL-XL), at the protein level. However, the posttranscriptional regulation of BAX is under explored. In this study, we identified BAX as the novel downstream [...] Read more.
Pro-apoptotic BCL2 associated X (BAX) is traditionally thought to be regulated by anti-apoptotic BCL-2 family members, like BCL2-like 1 (BCL-XL), at the protein level. However, the posttranscriptional regulation of BAX is under explored. In this study, we identified BAX as the novel downstream target of miR-365, which is supported by gain- and loss-of-function studies of onco-miR-365. Loss of BAX by either RNA interference or highly-expressed miR-365 in cells of cutaneous squamous cell carcinoma (CSCC) enhanced the tumor resistance against apoptosis, while repressing cell proliferation, migration, and invasiveness. In vivo experiment confirmed that BAX knockdown promotes the growth of CSCC xenografts. Collectively, our results find a miR-365-BAX axis for alleviating the pro-apoptotic effects of BAX, which promotes CSCC development and may facilitate the generation of novel therapeutic regimens to the clinical treatment of CSCC. Full article
Show Figures

Graphical abstract

457 KiB  
Review
Non-Coding RNAs in Hodgkin Lymphoma
by Anna Cordeiro, Mariano Monzó and Alfons Navarro
Int. J. Mol. Sci. 2017, 18(6), 1154; https://doi.org/10.3390/ijms18061154 - 29 May 2017
Cited by 14 | Viewed by 5123
Abstract
MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression by binding to the 3’-UTR of their target genes, can act as oncogenes or tumor suppressors. Recently, other types of non-coding RNAs—piwiRNAs and long non-coding RNAs—have also been identified. Hodgkin lymphoma (HL) is a [...] Read more.
MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression by binding to the 3’-UTR of their target genes, can act as oncogenes or tumor suppressors. Recently, other types of non-coding RNAs—piwiRNAs and long non-coding RNAs—have also been identified. Hodgkin lymphoma (HL) is a B cell origin disease characterized by the presence of only 1% of tumor cells, known as Hodgkin and Reed-Stenberg (HRS) cells, which interact with the microenvironment to evade apoptosis. Several studies have reported specific miRNA signatures that can differentiate HL lymph nodes from reactive lymph nodes, identify histologic groups within classical HL, and distinguish HRS cells from germinal center B cells. Moreover, some signatures are associated with survival or response to chemotherapy. Most of the miRNAs in the signatures regulate genes related to apoptosis, cell cycle arrest, or signaling pathways. Here we review findings on miRNAs in HL, as well as on other non-coding RNAs. Full article
Show Figures

Figure 1

1992 KiB  
Review
dFmr1 Plays Roles in Small RNA Pathways of Drosophila melanogaster
by Valeria Specchia, Simona D’Attis, Antonietta Puricella and Maria Pia Bozzetti
Int. J. Mol. Sci. 2017, 18(5), 1066; https://doi.org/10.3390/ijms18051066 - 16 May 2017
Cited by 12 | Viewed by 4662
Abstract
Fragile-X syndrome is the most common form of inherited mental retardation accompanied by other phenotypes, including macroorchidism. The disorder originates with mutations in the Fmr1 gene coding for the FMRP protein, which, with its paralogs FXR1 and FXR2, constitute a well-conserved family [...] Read more.
Fragile-X syndrome is the most common form of inherited mental retardation accompanied by other phenotypes, including macroorchidism. The disorder originates with mutations in the Fmr1 gene coding for the FMRP protein, which, with its paralogs FXR1 and FXR2, constitute a well-conserved family of RNA-binding proteins. Drosophila melanogaster is a good model for the syndrome because it has a unique fragile X-related gene: dFmr1. Recently, in addition to its confirmed role in the miRNA pathway, a function for dFmr1 in the piRNA pathway, operating in Drosophila gonads, has been established. In this review we report a summary of the piRNA pathways occurring in gonads with a special emphasis on the relationship between the piRNA genes and the crystal-Stellate system; we also analyze the roles of dFmr1 in the Drosophila gonads, exploring their genetic and biochemical interactions to reveal some unexpected connections. Full article
Show Figures

Graphical abstract

2109 KiB  
Article
Specific MicroRNA Pattern in Colon Tissue of Young Children with Eosinophilic Colitis
by Zoltán Kiss, Nóra Judit Béres, Erna Sziksz, Bálint Tél, Katalin Borka, András Arató, Attila J. Szabó and Gábor Veres
Int. J. Mol. Sci. 2017, 18(5), 1050; https://doi.org/10.3390/ijms18051050 - 12 May 2017
Cited by 2 | Viewed by 4599
Abstract
Eosinophilic colitis (EC) is a common cause of haematochezia in infants and young children. The exact pathomechanism is not understood, and the diagnosis is challenging. The role of microRNAs as key class of regulators of mRNA expression and translation in patients with EC [...] Read more.
Eosinophilic colitis (EC) is a common cause of haematochezia in infants and young children. The exact pathomechanism is not understood, and the diagnosis is challenging. The role of microRNAs as key class of regulators of mRNA expression and translation in patients with EC has not been explored. Therefore, the aim of the present study was to explore the miRNA profile in EC with respect to eosinophilic inflammation. Patients enrolled in the study (n = 10) had persistent rectal bleeding, and did not respond to elimination dietary treatment. High-throughput microRNA sequencing was carried out on colonic biopsy specimens of children with EC (EC: n = 4) and controls (C: n = 4) as a preliminary screening of the miRNA profile. Based on the next-generation sequencing (NGS) results and literature data, a potentially relevant panel of miRNAs were selected for further measurements by real-time reverse transcription (RT)-PCR (EC: n = 14, C: n = 10). Validation by RT-PCR resulted in significantly altered expression of miR-21, -31, -99b, -125a, -146a, -184, -221, -223, and -559 compared to controls (p ≤ 0.05). Elevation in miR-21, -99b, -146a, -221, and -223 showed statistically significant correlation to the extent of tissue eosinophilia. Based on our results, we conclude that the dysregulated miRNAs have a potential role in the regulation of apoptosis by targeting Protein kinase B/Mechanistic target of rapamycin (AKT/mTOR)-related pathways in inflammation by modulating Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related signalling and eosinophil cell recruitment and activation, mainly by regulating the expression of the chemoattractant eotaxin and the adhesion molecule CD44. Our results could serve as a basis for further extended research exploring the pathomechanism of EC. Full article
Show Figures

Figure 1

3565 KiB  
Article
miR-365 Ameliorates Dexamethasone-Induced Suppression of Osteogenesis in MC3T3-E1 Cells by Targeting HDAC4
by Daohua Xu, Yun Gao, Nan Hu, Longhuo Wu and Qian Chen
Int. J. Mol. Sci. 2017, 18(5), 977; https://doi.org/10.3390/ijms18050977 - 04 May 2017
Cited by 45 | Viewed by 5331
Abstract
Glucocorticoid administration is the leading cause of secondary osteoporosis. In this study, we tested the hypotheses that histone deacetylase 4 (HDAC4) is associated with glucocorticoid-induced bone loss and that HDAC4 dependent bone loss can be ameliorated by miRNA-365. Our previous studies showed that [...] Read more.
Glucocorticoid administration is the leading cause of secondary osteoporosis. In this study, we tested the hypotheses that histone deacetylase 4 (HDAC4) is associated with glucocorticoid-induced bone loss and that HDAC4 dependent bone loss can be ameliorated by miRNA-365. Our previous studies showed that miR-365 mediates mechanical stimulation of chondrocyte proliferation and differentiation by targeting HDAC4. However, it is not clear whether miR-365 has an effect on glucocorticoid-induced osteoporosis. We have shown that, in MC3T3-E1 osteoblasts, dexamethasone (DEX) treatment decreased the expression of miR-365, which is accompanied by the decrease of cell viability in a dose-dependent manner. Transfection of miR-365 ameliorated DEX-induced inhibition of MC3T3-E1 cell viability and alkaline phosphatase activity, and attenuated the suppressive effect of DEX on runt-related transcription factor 2 (Runx2), osteopontin (OPN), and collagen 1a1 (Col1a1) osteogenic gene expression. In addition, miR-365 decreased the expression of HDAC4 mRNA and protein by direct targeting the 3′-untranslated regions (3′-UTR) of HDAC4 mRNA in osteoblasts. MiR-365 increased Runx2 expression and such stimulatory effect could be reversed by HDAC4 over-expression in osteoblasts. Collectively, our findings indicate that miR-365 ameliorates DEX-induced suppression of cell viability and osteogenesis by regulating the expression of HDAC4 in osteoblasts, suggesting miR-365 might be a novel therapeutic agent for treatment of glucocorticoid-induced osteoporosis. Full article
Show Figures

Graphical abstract

1860 KiB  
Review
Small RNA Pathways That Protect the Somatic Genome
by Seogang Hyun
Int. J. Mol. Sci. 2017, 18(5), 912; https://doi.org/10.3390/ijms18050912 - 26 Apr 2017
Cited by 15 | Viewed by 5249
Abstract
Transposable elements (TEs) are DNA elements that can change their position within the genome, with the potential to create mutations and destabilize the genome. As such, special molecular systems have been adopted in animals to control TE activity in order to protect the [...] Read more.
Transposable elements (TEs) are DNA elements that can change their position within the genome, with the potential to create mutations and destabilize the genome. As such, special molecular systems have been adopted in animals to control TE activity in order to protect the genome. PIWI proteins, in collaboration with PIWI-interacting RNAs (piRNAs), are well known to play a critical role in silencing germline TEs. Although initially thought to be germline-specific, the role of PIWI–piRNA pathways in controlling TEs in somatic cells has recently begun to be explored in various organisms, together with the role of endogenous small interfering RNAs (endo-siRNAs). This review summarizes recent results suggesting that these small RNA pathways have been critically implicated in the silencing of somatic TEs underlying various physiological traits, with a special focus on the Drosophila model organism. Full article
Show Figures

Figure 1

520 KiB  
Review
Regulatory miRNAs in Colorectal Carcinogenesis and Metastasis
by Yongchen Guo, Yonghua Bao and Wancai Yang
Int. J. Mol. Sci. 2017, 18(4), 890; https://doi.org/10.3390/ijms18040890 - 22 Apr 2017
Cited by 28 | Viewed by 6488
Abstract
Colorectal cancer is one of the most common malignancies and is the second-leading cause of cancer-related death world-wide, which is linked to genetic mutations, epigenetic alterations, and oncogenic signaling activation. MicroRNAs, one of the categories of epigenetics, have been demonstrated significant roles in [...] Read more.
Colorectal cancer is one of the most common malignancies and is the second-leading cause of cancer-related death world-wide, which is linked to genetic mutations, epigenetic alterations, and oncogenic signaling activation. MicroRNAs, one of the categories of epigenetics, have been demonstrated significant roles in carcinogenesis and progression through regulating of oncogenic signaling pathways, stem cells, epithelial-mesenchymal transition, and metastasis. This review summarizes the roles of microRNAs in the regulating of Wnt, Ras, TGF-β, and inflammatory signaling pathways, stemness, and epithelial-mesenchymal transition, for carcinogenesis and metastasis in colorectal cancer. Improving our understanding of the mechanisms of regulatory interactions of microRNAs with signaling pathways in colorectal cancer formation and progression will aid in determining the genes responsible for colorectal cancer initiation, progression, metastasis, and recurrence and, finally, in developing personalized approaches for cancer prevention and therapy. Full article
Show Figures

Graphical abstract

4780 KiB  
Article
Long Coding RNA XIST Contributes to Neuronal Apoptosis through the Downregulation of AKT Phosphorylation and Is Negatively Regulated by miR-494 in Rat Spinal Cord Injury
by Shixin Gu, Rong Xie, Xiaodong Liu, Jiajun Shou, Wentao Gu and Xiaoming Che
Int. J. Mol. Sci. 2017, 18(4), 732; https://doi.org/10.3390/ijms18040732 - 01 Apr 2017
Cited by 109 | Viewed by 6009
Abstract
Recent evidence has suggested that long non-coding RNAs (lncRNAs) may play a significant role in the pathogenesis of several neurological diseases, including spinal cord injury (SCI). However, little is known about the role of lncRNAs in SCI. The aim of the present study [...] Read more.
Recent evidence has suggested that long non-coding RNAs (lncRNAs) may play a significant role in the pathogenesis of several neurological diseases, including spinal cord injury (SCI). However, little is known about the role of lncRNAs in SCI. The aim of the present study was to evaluate the potential functions of lncRNAs in SCI and to identify the underlying mechanisms of action. We firstly analyzed Gene Expression Omnibus (GEO) datasets to investigate aberrantly-expressed lncRNAs which might be involved in the pathogenesis of SCI. The long non-coding RNA X-inactive specific transcript (XIST) was found to be one of the most significantly upregulated lncRNAs in the GEO dataset analysis, and is associated with apoptosis. We, therefore, selected this as a candidate lncRNA and investigated its function. We found that knockdown of lncRNA-XIST by Lv-shRNA had a prominent protective effect on SCI recovery by suppressing apoptosis through reactivation of the PI3K/AKT signaling pathway in rat spinal cord tissue. In particular, our results suggested that lncRNA-XIST may act as a competitive endogenous RNA, effectively becoming a sink for miR-494, leading to derepression of its target gene, phosphatase and tensin homolog deleted on chromosome ten (PTEN). In addition, an inverse relationship between lncRNA-XIST and miR-494 was observed in spinal cord tissues of SCI rats. Further study demonstrated that antagomiR-494 could reverse the protective effects of lncRNA-XIST knockdown on SCI rats through blocking the PTEN/PI3K/AKT signaling pathway. These results suggested that lncRNA-XIST knockdown may play an important role in limiting neuronal apoptosis in rats following SCI, and that the observed protective effects of lncRNA-XIST knockdown might have been mediated by its regulation on the phosphorylation of AKT by competitively binding miR-494. These findings have revealed, for the first time, the importance of the XIST/miR-494/PTEN/AKT signaling axis in the pathogenesis of SCI and suggest that lncRNA-XIST may be a promising molecular target for SCI therapy. Full article
Show Figures

Figure 1

865 KiB  
Review
Potentials of Long Noncoding RNAs (LncRNAs) in Sarcoma: From Biomarkers to Therapeutic Targets
by Li Min, Cassandra Garbutt, Chongqi Tu, Francis Hornicek and Zhenfeng Duan
Int. J. Mol. Sci. 2017, 18(4), 731; https://doi.org/10.3390/ijms18040731 - 29 Mar 2017
Cited by 29 | Viewed by 5450
Abstract
Sarcoma includes some of the most heterogeneous tumors, which make the diagnosis, prognosis and treatment of these rare yet diverse neoplasms especially challenging. Long noncoding RNAs (lncRNAs) are important regulators of cancer initiation and progression, which implies their potential as neoteric prognostic and [...] Read more.
Sarcoma includes some of the most heterogeneous tumors, which make the diagnosis, prognosis and treatment of these rare yet diverse neoplasms especially challenging. Long noncoding RNAs (lncRNAs) are important regulators of cancer initiation and progression, which implies their potential as neoteric prognostic and diagnostic markers in cancer, including sarcoma. A relationship between lncRNAs and sarcoma pathogenesis and progression is emerging. Recent studies demonstrate that lncRNAs influence sarcoma cell proliferation, metastasis, and drug resistance. Additionally, lncRNA expression profiles are predictive of sarcoma prognosis. In this review, we summarize contemporary advances in the research of lncRNA biogenesis and functions in sarcoma. We also highlight the potential for lncRNAs to become innovative diagnostic and prognostic biomarkers as well as therapeutic targets in sarcoma. Full article
Show Figures

Graphical abstract

704 KiB  
Review
Function and Clinical Implications of Long Non-Coding RNAs in Melanoma
by Georg Richtig, Barbara Ehall, Erika Richtig, Ariane Aigelsreiter, Tony Gutschner and Martin Pichler
Int. J. Mol. Sci. 2017, 18(4), 715; https://doi.org/10.3390/ijms18040715 - 28 Mar 2017
Cited by 33 | Viewed by 5781
Abstract
Metastatic melanoma is the most deadly type of skin cancer. Despite the success of immunotherapy and targeted agents, the majority of patients experience disease recurrence upon treatment and die due to their disease. Long non-coding RNAs (lncRNAs) are a new subclass of non-protein [...] Read more.
Metastatic melanoma is the most deadly type of skin cancer. Despite the success of immunotherapy and targeted agents, the majority of patients experience disease recurrence upon treatment and die due to their disease. Long non-coding RNAs (lncRNAs) are a new subclass of non-protein coding RNAs involved in (epigenetic) regulation of cell growth, invasion, and other important cellular functions. Consequently, recent research activities focused on the discovery of these lncRNAs in a broad spectrum of human diseases, especially cancer. Additional efforts have been undertaken to dissect the underlying molecular mechanisms employed by lncRNAs. In this review, we will summarize the growing evidence of deregulated lncRNA expression in melanoma, which is linked to tumor growth and progression. Moreover, we will highlight specific molecular pathways and modes of action for some well-studied lncRNAs and discuss their potential clinical implications. Full article
Show Figures

Figure 1

7800 KiB  
Article
Evaluation and Adaptation of a Laboratory-Based cDNA Library Preparation Protocol for Retrospective Sequencing of Archived MicroRNAs from up to 35-Year-Old Clinical FFPE Specimens
by Olivier Loudig, Tao Wang, Kenny Ye, Juan Lin, Yihong Wang, Andrew Ramnauth, Christina Liu, Azadeh Stark, Dhananjay Chitale, Robert Greenlee, Deborah Multerer, Stacey Honda, Yihe Daida, Heather Spencer Feigelson, Andrew Glass, Fergus J. Couch, Thomas Rohan and Iddo Z. Ben-Dov
Int. J. Mol. Sci. 2017, 18(3), 627; https://doi.org/10.3390/ijms18030627 - 14 Mar 2017
Cited by 13 | Viewed by 5829
Abstract
Formalin-fixed paraffin-embedded (FFPE) specimens, when used in conjunction with patient clinical data history, represent an invaluable resource for molecular studies of cancer. Even though nucleic acids extracted from archived FFPE tissues are degraded, their molecular analysis has become possible. In this study, we [...] Read more.
Formalin-fixed paraffin-embedded (FFPE) specimens, when used in conjunction with patient clinical data history, represent an invaluable resource for molecular studies of cancer. Even though nucleic acids extracted from archived FFPE tissues are degraded, their molecular analysis has become possible. In this study, we optimized a laboratory-based next-generation sequencing barcoded cDNA library preparation protocol for analysis of small RNAs recovered from archived FFPE tissues. Using matched fresh and FFPE specimens, we evaluated the robustness and reproducibility of our optimized approach, as well as its applicability to archived clinical specimens stored for up to 35 years. We then evaluated this cDNA library preparation protocol by performing a miRNA expression analysis of archived breast ductal carcinoma in situ (DCIS) specimens, selected for their relation to the risk of subsequent breast cancer development and obtained from six different institutions. Our analyses identified six miRNAs (miR-29a, miR-221, miR-375, miR-184, miR-363, miR-455-5p) differentially expressed between DCIS lesions from women who subsequently developed an invasive breast cancer (cases) and women who did not develop invasive breast cancer within the same time interval (control). Our thorough evaluation and application of this laboratory-based miRNA sequencing analysis indicates that the preparation of small RNA cDNA libraries can reliably be performed on older, archived, clinically-classified specimens. Full article
Show Figures

Figure 1

1112 KiB  
Review
The Role and Molecular Mechanism of Non-Coding RNAs in Pathological Cardiac Remodeling
by Jinning Gao, Wenhua Xu, Jianxun Wang, Kun Wang and Peifeng Li
Int. J. Mol. Sci. 2017, 18(3), 608; https://doi.org/10.3390/ijms18030608 - 10 Mar 2017
Cited by 51 | Viewed by 6882
Abstract
Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. Studies show that ncRNAs are not only involved in cell proliferation, apoptosis, differentiation, metabolism and other physiological processes, but also involved in the pathogenesis of diseases. Cardiac remodeling is [...] Read more.
Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. Studies show that ncRNAs are not only involved in cell proliferation, apoptosis, differentiation, metabolism and other physiological processes, but also involved in the pathogenesis of diseases. Cardiac remodeling is the main pathological basis of a variety of cardiovascular diseases. Many studies have shown that the occurrence and development of cardiac remodeling are closely related with the regulation of ncRNAs. Recent research of ncRNAs in heart disease has achieved rapid development. Thus, we summarize here the latest research progress and mainly the molecular mechanism of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), in cardiac remodeling, aiming to look for new targets for heart disease treatment. Full article
Show Figures

Figure 1

3582 KiB  
Review
Exosomes: From Garbage Bins to Promising Therapeutic Targets
by Mohammed H. Rashed, Emine Bayraktar, Gouda K. Helal, Mohamed F. Abd-Ellah, Paola Amero, Arturo Chavez-Reyes and Cristian Rodriguez-Aguayo
Int. J. Mol. Sci. 2017, 18(3), 538; https://doi.org/10.3390/ijms18030538 - 02 Mar 2017
Cited by 378 | Viewed by 19302
Abstract
Intercellular communication via cell-released vesicles is a very important process for both normal and tumor cells. Cell communication may involve exosomes, small vesicles of endocytic origin that are released by all types of cells and are found in abundance in body fluids, including [...] Read more.
Intercellular communication via cell-released vesicles is a very important process for both normal and tumor cells. Cell communication may involve exosomes, small vesicles of endocytic origin that are released by all types of cells and are found in abundance in body fluids, including blood, saliva, urine, and breast milk. Exosomes have been shown to carry lipids, proteins, mRNAs, non-coding RNAs, and even DNA out of cells. They are more than simply molecular garbage bins, however, in that the molecules they carry can be taken up by other cells. Thus, exosomes transfer biological information to neighboring cells and through this cell-to-cell communication are involved not only in physiological functions such as cell-to-cell communication, but also in the pathogenesis of some diseases, including tumors and neurodegenerative conditions. Our increasing understanding of why cells release exosomes and their role in intercellular communication has revealed the very complex and sophisticated contribution of exosomes to health and disease. The aim of this review is to reveal the emerging roles of exosomes in normal and pathological conditions and describe the controversial biological role of exosomes, as it is now understood, in carcinogenesis. We also summarize what is known about exosome biogenesis, composition, functions, and pathways and discuss the potential clinical applications of exosomes, especially as biomarkers and novel therapeutic agents. Full article
Show Figures

Graphical abstract

496 KiB  
Review
Current Insights into Long Non-Coding RNAs (LncRNAs) in Prostate Cancer
by Maria A. Smolle, Thomas Bauernhofer, Karl Pummer, George A. Calin and Martin Pichler
Int. J. Mol. Sci. 2017, 18(2), 473; https://doi.org/10.3390/ijms18020473 - 22 Feb 2017
Cited by 71 | Viewed by 7214
Abstract
The importance of long non-coding RNAs (lncRNAs) in the pathogenesis of various malignancies has been uncovered over the last few years. Their dysregulation often contributes to or is a result of tumour progression. In prostate cancer, the most common malignancy in men, lncRNAs [...] Read more.
The importance of long non-coding RNAs (lncRNAs) in the pathogenesis of various malignancies has been uncovered over the last few years. Their dysregulation often contributes to or is a result of tumour progression. In prostate cancer, the most common malignancy in men, lncRNAs can promote castration resistance, cell proliferation, invasion, and metastatic spread. Expression patterns of lncRNAs often change during tumour progression; their expression levels may constantly rise (e.g., HOX transcript antisense RNA, HOTAIR), or steadily decrease (e.g., downregulated RNA in cancer, DRAIC). In prostate cancer, lncRNAs likewise have diagnostic (e.g., prostate cancer antigen 3, PCA3), prognostic (e.g., second chromosome locus associated with prostate-1, SChLAP1), and predictive (e.g., metastasis-associated lung adenocarcinoma transcript-1, MALAT-1) functions. Considering their dynamic role in prostate cancer, lncRNAs may also serve as therapeutic targets, helping to prevent development of castration resistance, maintain stable disease, and prohibit metastatic spread. Full article
Show Figures

Figure 1

2032 KiB  
Review
MicroRNAs: New Insight in Modulating Follicular Atresia: A Review
by Tesfaye Worku, Zia Ur Rehman, Hira Sajjad Talpur, Dinesh Bhattarai, Farman Ullah, Ngabu Malobi, Tesfaye Kebede and Liguo Yang
Int. J. Mol. Sci. 2017, 18(2), 333; https://doi.org/10.3390/ijms18020333 - 09 Feb 2017
Cited by 49 | Viewed by 7094
Abstract
Our understanding of the post-transcriptional mechanisms involved in follicular atresia is limited; however, an important development has been made in understanding the biological regulatory networks responsible for mediating follicular atresia. MicroRNAs have come to be seen as a key regulatory actor in determining [...] Read more.
Our understanding of the post-transcriptional mechanisms involved in follicular atresia is limited; however, an important development has been made in understanding the biological regulatory networks responsible for mediating follicular atresia. MicroRNAs have come to be seen as a key regulatory actor in determining cell fate in a wide range of tissues in normal and pathological processes. Profiling studies of miRNAs during follicular atresia and development have identified several putative miRNAs enriched in apoptosis signaling pathways. Subsequent in vitro and/or in vivo studies of granulosa cells have elucidated the functional role of some miRNAs along with their molecular pathways. In particular, the regulatory roles of some miRNAs have been consistently observed during studies of follicular cellular apoptosis. Continued work should gradually lead to better understanding of the role of miRNAs in this field. Ultimately, we expect this understanding will have substantial benefits for fertility management at both the in vivo or/and in vitro levels. The stable nature of miRNA holds remarkable promise in clinical use as a diagnostic tool and in reproductive medicine to solve the ever-increasing fertility problem. In this review, we summarize current knowledge of the involvement of miRNAs in follicular atresia, discuss the challenges for further work and pinpoint areas for future research. Full article
Show Figures

Graphical abstract

4051 KiB  
Article
The Long Non-Coding RNA RHPN1-AS1 Promotes Uveal Melanoma Progression
by Linna Lu, Xiaoyu Yu, Leilei Zhang, Xia Ding, Hui Pan, Xuyang Wen, Shiqiong Xu, Yue Xing, Jiayan Fan, Shengfang Ge, He Zhang, Renbing Jia and Xianqun Fan
Int. J. Mol. Sci. 2017, 18(1), 226; https://doi.org/10.3390/ijms18010226 - 23 Jan 2017
Cited by 57 | Viewed by 6472
Abstract
Increasing evidence suggests that aberrant long non-coding RNAs (lncRNAs) are significantly correlated with the pathogenesis, development and metastasis of cancers. RHPN1 antisense RNA 1 (RHPN1-AS1) is a 2030-bp transcript originating from human chromosome 8q24. However, the role of RHPN1-AS1 in uveal [...] Read more.
Increasing evidence suggests that aberrant long non-coding RNAs (lncRNAs) are significantly correlated with the pathogenesis, development and metastasis of cancers. RHPN1 antisense RNA 1 (RHPN1-AS1) is a 2030-bp transcript originating from human chromosome 8q24. However, the role of RHPN1-AS1 in uveal melanoma (UM) remains to be clarified. In this study, we aimed to elucidate the molecular function of RHPN1-AS1 in UM. The RNA levels of RHPN1-AS1 in UM cell lines were examined using the quantitative real-time polymerase chain reaction (qRT-PCR). Short interfering RNAs (siRNAs) were designed to quench RHPN1-AS1 expression, and UM cells stably expressing short hairpin (sh) RHPN1-AS1 were established. Next, the cell proliferation and migration abilities were determined using a colony formation assay and a transwell migration/invasion assay. A tumor xenograft model in nude mice was established to confirm the function of RHPN1-AS1 in vivo. RHPN1-AS1 was significantly upregulated in a number of UM cell lines compared with the normal human retinal pigment epithelium (RPE) cell line. RHPN1-AS1 knockdown significantly inhibited UM cell proliferation and migration in vitro and in vivo. Our data suggest that RHPN1-AS1 could be an oncoRNA in UM, which may serve as a candidate prognostic biomarker and target for new therapies in malignant UM. Full article
Show Figures

Graphical abstract

4280 KiB  
Article
A Novel Combination RNAi toward Warburg Effect by Replacement with miR-145 and Silencing of PTBP1 Induces Apoptotic Cell Death in Bladder Cancer Cells
by Tomoaki Takai, Yuki Yoshikawa, Teruo Inamoto, Koichiro Minami, Kohei Taniguchi, Nobuhiko Sugito, Yuki Kuranaga, Haruka Shinohara, Minami Kumazaki, Takuya Tsujino, Kiyoshi Takahara, Yuko Ito, Yukihiro Akao and Haruhito Azuma
Int. J. Mol. Sci. 2017, 18(1), 179; https://doi.org/10.3390/ijms18010179 - 17 Jan 2017
Cited by 37 | Viewed by 6346
Abstract
Bladder cancer is one of the most difficult malignancies to control. We explored the use of a novel RNA-interference method for a driver oncogene regulating cancer specific energy metabolism by the combination treatment with a small interfering RNA (siRNA) and a microRNA. After [...] Read more.
Bladder cancer is one of the most difficult malignancies to control. We explored the use of a novel RNA-interference method for a driver oncogene regulating cancer specific energy metabolism by the combination treatment with a small interfering RNA (siRNA) and a microRNA. After transfection of T24 and 253JB-V cells with miR-145 and/or siR-PTBP1, we examined the effects of cell growth and gene expression by performing the trypan blue dye exclusion test, Western blot, Hoechst 33342 staining, reverse transcription polymerase chain reaction (RT-PCR), and electron microscopy. The anti-cancer effects of xenograft model mice with miR-145 and/or siR-PTBP1 were then assessed. The combination treatment induced the deeper and longer growth inhibition and reduced the levels of both mRNA and protein expression of c-Myc and polypyrimidine tract-binding protein 1 (PTBP1) more than each single treatment. Notably, the combination treatment not only impaired the cancer specific energy metabolism by inhibiting c-Myc/PTBP1/PKMs axis but also inactivated MAPK/ERK and PI3K/AKT pathways examined in vitro and in vivo. Furthermore, the combination treatment induced apoptosis or autophagy; but, in some cells, apoptotic cell death was accompanied by autophagy, because the condensation of chromatin and many autophagosomes were coexistent. This combination treatment could be a novel RNA-interference strategy through the systemic silencing of the Warburg effect-promoting driver oncogene PTBP1 in bladder cancer cells. Full article
Show Figures

Figure 1

9138 KiB  
Article
Role of miR-34a-5p in Hematopoietic Progenitor Cells Proliferation and Fate Decision: Novel Insights into the Pathogenesis of Primary Myelofibrosis
by Elisa Bianchi, Samantha Ruberti, Sebastiano Rontauroli, Paola Guglielmelli, Simona Salati, Chiara Rossi, Roberta Zini, Enrico Tagliafico, Alessandro Maria Vannucchi and Rossella Manfredini
Int. J. Mol. Sci. 2017, 18(1), 145; https://doi.org/10.3390/ijms18010145 - 13 Jan 2017
Cited by 13 | Viewed by 5433
Abstract
Primary Myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by a skewed megakaryopoiesis and an overproduction of proinflammatory and profibrotic mediators that lead to the development of bone marrow (BM) fibrosis. Since we recently uncovered the upregulation of miR-34a-5p in PMF CD34+ [...] Read more.
Primary Myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by a skewed megakaryopoiesis and an overproduction of proinflammatory and profibrotic mediators that lead to the development of bone marrow (BM) fibrosis. Since we recently uncovered the upregulation of miR-34a-5p in PMF CD34+ hematopoietic progenitor cells (HPCs), in order to elucidate its role in PMF pathogenesis here we unravelled the effects of miR-34a-5p overexpression in HPCs. We showed that enforced expression of miR-34a-5p partially constrains proliferation and favours the megakaryocyte and monocyte/macrophage commitment of HPCs. Interestingly, we identified lymphoid enhancer-binding factor 1 (LEF1) and nuclear receptor subfamily 4, group A, member 2 (NR4A2) transcripts as miR-34a-5p-targets downregulated after miR-34a-5p overexpression in HPCs as well as in PMF CD34+ cells. Remarkably, the knockdown of NR4A2 in HPCs mimicked the antiproliferative effects of miR-34a-5p overexpression, while the silencing of LEF1 phenocopied the effects of miR-34a-5p overexpression on HPCs lineage choice, by favouring the megakaryocyte and monocyte/macrophage commitment. Collectively our data unravel the role of miR-34a-5p in HPCs fate decision and suggest that the increased expression of miR-34a-5p in PMF HPCs could be important for the skewing of megakaryopoiesis and the production of monocytes, that are key players in BM fibrosis in PMF patients. Full article
Show Figures

Figure 1

2016

Jump to: 2023, 2022, 2021, 2020, 2019, 2018, 2017, 2015, 2014

676 KiB  
Review
Therapeutic Resistance in Acute Myeloid Leukemia: The Role of Non-Coding RNAs
by Armin Zebisch, Stefan Hatzl, Martin Pichler, Albert Wölfler and Heinz Sill
Int. J. Mol. Sci. 2016, 17(12), 2080; https://doi.org/10.3390/ijms17122080 - 10 Dec 2016
Cited by 56 | Viewed by 6788
Abstract
Acute myeloid leukemia (AML) is caused by malignant transformation of hematopoietic stem or progenitor cells and displays the most frequent acute leukemia in adults. Although some patients can be cured with high dose chemotherapy and allogeneic hematopoietic stem cell transplantation, the majority still [...] Read more.
Acute myeloid leukemia (AML) is caused by malignant transformation of hematopoietic stem or progenitor cells and displays the most frequent acute leukemia in adults. Although some patients can be cured with high dose chemotherapy and allogeneic hematopoietic stem cell transplantation, the majority still succumbs to chemoresistant disease. Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNA fragments and act as key players in the regulation of both physiologic and pathologic gene expression profiles. Aberrant expression of various non-coding RNAs proved to be of seminal importance in the pathogenesis of AML, as well in the development of resistance to chemotherapy. In this review, we discuss the role of miRNAs and lncRNAs with respect to sensitivity and resistance to treatment regimens currently used in AML and provide an outlook on potential therapeutic targets emerging thereof. Full article
Show Figures

Figure 1

7866 KiB  
Article
Relevance of MicroRNA200 Family and MicroRNA205 for Epithelial to Mesenchymal Transition and Clinical Outcome in Biliary Tract Cancer Patients
by Romana Urbas, Christian Mayr, Eckhard Klieser, Julia Fuereder, Doris Bach, Stefan Stättner, Florian Primavesi, Tarkan Jaeger, Stefanie Stanzer, Anna Lena Ress, Magdalena Löffelberger, Andrej Wagner, Frieder Berr, Markus Ritter, Martin Pichler, Daniel Neureiter and Tobias Kiesslich
Int. J. Mol. Sci. 2016, 17(12), 2053; https://doi.org/10.3390/ijms17122053 - 07 Dec 2016
Cited by 14 | Viewed by 5751
Abstract
Extensive stromal interaction is one reason for the dismal outcome of biliary tract cancer (BTC) patients. Epithelial to mesenchymal transition (EMT) is involved in tumor invasion and metastasis and is partly regulated by microRNAs (miRs). This study explores the expression of anti-EMT miR200 [...] Read more.
Extensive stromal interaction is one reason for the dismal outcome of biliary tract cancer (BTC) patients. Epithelial to mesenchymal transition (EMT) is involved in tumor invasion and metastasis and is partly regulated by microRNAs (miRs). This study explores the expression of anti-EMT miR200 family (miR141, −200a/b/c, −429) and miR205 as well as the EMT-related proteins E-cadherin and vimentin in a panel of BTC cell lines and clinical specimens by quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry, respectively. MicroRNA expression was correlated to (i) the expression patterns of E-cadherin and vimentin; (ii) clinicopathological characteristics; and (iii) survival data. MicroRNA-200 family and miR205 were expressed in all BTC cells and clinical specimens. E-cadherin and vimentin showed a mutually exclusive expression pattern in both, in vitro and in vivo. Expression of miR200 family members positively correlated with E-cadherin and negatively with vimentin expression in BTC cells and specimens. High expression of miR200 family members (but not miR205) and E-cadherin was associated with longer survival, while low miR200 family and high vimentin expression was a predictor of unfavorable survival. Overall, the current study demonstrates the relevance of the miR200 family in EMT of BTC tumors and suggests these miRs as predictors for positive outcome. Full article
Show Figures

Graphical abstract

2970 KiB  
Article
Screening the Expression Changes in MicroRNAs and Their Target Genes in Mature Cementoblasts Stimulated with Cyclic Tensile Stress
by Liao Wang, Haikun Hu, Ye Cheng, Jianwei Chen, Chongyun Bao, Shujuan Zou and Gang Wu
Int. J. Mol. Sci. 2016, 17(12), 2024; https://doi.org/10.3390/ijms17122024 - 07 Dec 2016
Cited by 11 | Viewed by 4900
Abstract
Cementum is a thin layer of cementoblast-produced mineralized tissue covering the root surfaces of teeth. Mechanical forces, which are produced during masticatory activity, play a paramount role in stimulating cementoblastogenesis, which thereby facilitates the maintenance, remodeling and integrity of cementum. However, hitherto, the [...] Read more.
Cementum is a thin layer of cementoblast-produced mineralized tissue covering the root surfaces of teeth. Mechanical forces, which are produced during masticatory activity, play a paramount role in stimulating cementoblastogenesis, which thereby facilitates the maintenance, remodeling and integrity of cementum. However, hitherto, the extent to which a post-transcriptional modulation mechanism is involved in this process has rarely been reported. In this study, a mature murine cementoblast cell line OCCM-30 cells (immortalized osteocalcin positive cementoblasts) was cultured and subjected to cyclic tensile stress (0.5 Hz, 2000 µstrain). We showed that the cyclic tensile stress could not only rearrange the cell alignment, but also influence the proliferation in an S-shaped manner. Furthermore, cyclic tensile stress could significantly promote cementoblastogenesis-related genes, proteins and mineralized nodules. From the miRNA array analyses, we found that 60 and 103 miRNAs were significantly altered 6 and 18 h after the stimulation using cyclic tensile stress, respectively. Based on a literature review and bioinformatics analyses, we found that miR-146b-5p and its target gene Smad4 play an important role in this procedure. The upregulation of miR-146b-5p and downregulation of Smad4 induced by the tensile stress were further confirmed by qRT-PCR. The direct binding of miR-146b-5p to the three prime untranslated region (3′ UTR) of Smad4 was established using a dual-luciferase reporter assay. Taken together, these results suggest an important involvement of miR-146b-5p and its target gene Smad4 in the cementoblastogenesis of mature cementoblasts. Full article
Show Figures

Graphical abstract

4359 KiB  
Article
Comprehensive Analysis of miRNome Alterations in Response to Sorafenib Treatment in Colorectal Cancer Cells
by Anna-Maria Pehserl, Anna Lena Ress, Stefanie Stanzer, Margit Resel, Michael Karbiener, Elke Stadelmeyer, Verena Stiegelbauer, Armin Gerger, Christian Mayr, Marcel Scheideler, Georg C. Hutterer, Thomas Bauernhofer, Tobias Kiesslich and Martin Pichler
Int. J. Mol. Sci. 2016, 17(12), 2011; https://doi.org/10.3390/ijms17122011 - 01 Dec 2016
Cited by 30 | Viewed by 5434
Abstract
MicroRNAs (miRNAs) are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer (CRC). Sorafenib, a multi-kinase inhibitor which has been approved for the treatment of liver, renal and thyroid cancer, [...] Read more.
MicroRNAs (miRNAs) are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer (CRC). Sorafenib, a multi-kinase inhibitor which has been approved for the treatment of liver, renal and thyroid cancer, is currently being studied as a monotherapy in selected molecular subtypes or in combination with other drugs in metastatic CRC. In this study, we explored sorafenib-induced cellular effects in Kirsten rat sarcoma viral oncogene homolog olog (KRAS) wild-type and KRAS-mutated CRC cell lines (Caco-2 and HRT-18), and finally profiled expression changes of specific miRNAs within the miRNome (>1000 human miRNAs) after exposure to sorafenib. Overall, sorafenib induced a time- and dose-dependent growth-inhibitory effect through S-phase cell cycle arrest in KRAS wild-type and KRAS-mutated CRC cells. In HRT-18 cells, two human miRNAs (hsa-miR-597 and hsa-miR-720) and two small RNAs (SNORD 13 and hsa-miR-3182) were identified as specifically sorafenib-induced. In Caco-2 cells, nine human miRNAs (hsa-miR-3142, hsa-miR-20a, hsa-miR-4301, hsa-miR-1290, hsa-miR-4286, hsa-miR-3182, hsa-miR-3142, hsa-miR-1246 and hsa-miR-720) were identified to be differentially regulated post sorafenib treatment. In conclusion, we confirmed sorafenib as a potential anti-neoplastic treatment strategy for CRC cells by demonstrating a growth-inhibitory and cell cycle–arresting effect of this drug. Changes in the miRNome indicate that some specific miRNAs might be relevant as indicators for sorafenib response, drug resistance and potential targets for combinatorial miRNA-based drug strategies. Full article
Show Figures

Graphical abstract

824 KiB  
Review
Roles of MicroRNA across Prenatal and Postnatal Periods
by Ilaria Floris, Jamie D. Kraft and Illimar Altosaar
Int. J. Mol. Sci. 2016, 17(12), 1994; https://doi.org/10.3390/ijms17121994 - 28 Nov 2016
Cited by 31 | Viewed by 6861
Abstract
Communication between mother and offspring in mammals starts at implantation via the maternal–placental–fetal axis, and continues postpartum via milk targeted to the intestinal mucosa. MicroRNAs (miRNAs), short, noncoding single-stranded RNAs, of about 22 nucleotides in length, are actively involved in many developmental and [...] Read more.
Communication between mother and offspring in mammals starts at implantation via the maternal–placental–fetal axis, and continues postpartum via milk targeted to the intestinal mucosa. MicroRNAs (miRNAs), short, noncoding single-stranded RNAs, of about 22 nucleotides in length, are actively involved in many developmental and physiological processes. Here we highlight the role of miRNA in the dynamic signaling that guides infant development, starting from implantation of conceptus and persisting through the prenatal and postnatal periods. miRNAs in body fluids, particularly in amniotic fluid, umbilical cord blood, and breast milk may offer new opportunities to investigate physiological and/or pathological molecular mechanisms that portend to open novel research avenues for the identification of noninvasive biomarkers. Full article
Show Figures

Graphical abstract

3397 KiB  
Article
Microarray Expression Profiling of Long Non-Coding RNAs Involved in Nasopharyngeal Carcinoma Metastasis
by Xin Wen, Xinran Tang, Yingqin Li, Xianyue Ren, Qingmei He, Xiaojing Yang, Jian Zhang, Yaqin Wang, Jun Ma and Na Liu
Int. J. Mol. Sci. 2016, 17(11), 1956; https://doi.org/10.3390/ijms17111956 - 23 Nov 2016
Cited by 30 | Viewed by 6270
Abstract
Increasing evidence has demonstrated a significant role for long non-coding RNAs (lncRNAs) in tumorigenesis. However, their functions in nasopharyngeal carcinoma (NPC) metastasis remain largely unknown. In this study, a model comparing high and low metastatic NPC cell lines (5-8F vs. 6-10B and S18 [...] Read more.
Increasing evidence has demonstrated a significant role for long non-coding RNAs (lncRNAs) in tumorigenesis. However, their functions in nasopharyngeal carcinoma (NPC) metastasis remain largely unknown. In this study, a model comparing high and low metastatic NPC cell lines (5-8F vs. 6-10B and S18 vs. S26) was constructed to determine the expression profile of lncRNAs using the microarray analysis, and we found 167 lncRNAs and 209 mRNAs were differentially expressed. Bioinformatic analysis indicated that the dysregulated mRNAs participated in important biological regulatory functions in NPC. Validation of 26 significantly dysregulated lncRNAs by qRT-PCR showed the expression patterns of 22 lncRNAs were in accordance with the microarray data. Furthermore, the expression level of ENST00000470135, which was the most upregulated lncRNA in high metastatic cell lines, was significantly higher in NPC cell lines and tissues with lymph node metastasis (LNM) and knocking down ENST00000470135 suppressed the migration, invasion and proliferation of NPC cells in vitro. In conclusion, our study revealed expression patterns of lncRNAs in NPC metastasis. The dysregulated lncRNAs may act as novel biomarkers and therapeutic targets for NPC. Full article
Show Figures

Figure 1

1303 KiB  
Article
MicroRNAs 10a and 10b Regulate the Expression of Human Platelet Glycoprotein Ibα for Normal Megakaryopoiesis
by Zuping Zhang, Yali Ran, Tanner S. Shaw and Yuandong Peng
Int. J. Mol. Sci. 2016, 17(11), 1873; https://doi.org/10.3390/ijms17111873 - 09 Nov 2016
Cited by 16 | Viewed by 4168
Abstract
MicroRNAs are a class of small non-coding RNAs that bind to the three prime untranslated region (3′-UTR) of target mRNAs. They cause a cleavage or an inhibition of the translation of target mRNAs, thus regulating gene expression. Here, we employed three prediction tools [...] Read more.
MicroRNAs are a class of small non-coding RNAs that bind to the three prime untranslated region (3′-UTR) of target mRNAs. They cause a cleavage or an inhibition of the translation of target mRNAs, thus regulating gene expression. Here, we employed three prediction tools to search for potential miRNA target sites in the 3′-UTR of the human platelet glycoprotein (GP) 1BA gene. A luciferase reporter assay shows that miR-10a and -10b sites are functional. When miR-10a or -10b mimics were transfected into the GP Ibβ/GP IX-expressing cells, along with a DNA construct harboring both the coding and 3′-UTR sequences of the human GP1BA gene, we found that they inhibit the transient expression of GP Ibα on the cell surface. When the miR-10a or -10b mimics were introduced into murine progenitor cells, upon megakaryocyte differentiation, we found that GP Ibα mRNA expression was markedly reduced, suggesting that a miRNA-induced mRNA degradation is at work. Thus, our study identifies GP Ibα as a novel target of miR-10a and -10b, suggesting that a drastic reduction in the levels of miR-10a and -10b in the late stage of megakaryopoiesis is required to allow the expression of human GP Ibα and the formation of the GP Ib-IX-V complex. Full article
Show Figures

Figure 1

2912 KiB  
Article
X-Linked miRNAs Associated with Gender Differences in Rheumatoid Arthritis
by Olfa Khalifa, Yves-Marie Pers, Rosanna Ferreira, Audrey Sénéchal, Christian Jorgensen, Florence Apparailly and Isabelle Duroux-Richard
Int. J. Mol. Sci. 2016, 17(11), 1852; https://doi.org/10.3390/ijms17111852 - 08 Nov 2016
Cited by 56 | Viewed by 6479
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease that predominantly affects women. MicroRNAs have emerged as crucial regulators of the immune system, whose expression is deregulated in RA. We aimed at quantifying the expression level of 14 miRNAs located on the X chromosome and [...] Read more.
Rheumatoid arthritis (RA) is an autoimmune disease that predominantly affects women. MicroRNAs have emerged as crucial regulators of the immune system, whose expression is deregulated in RA. We aimed at quantifying the expression level of 14 miRNAs located on the X chromosome and at identifying whether differences are associated with disease and/or sex. A case–control study of 21 RA patients and 22 age- and sex-matched healthy controls was performed on peripheral blood mononuclear cells. The expression level of five miRNAs (miR-221, miR-222, miR-532, miR-106a, and miR-98) was significantly different between RA and controls when stratifying by sex, and the expression level of four miRNAs (miR-222, miR-532, miR-98, and miR-92a) was significantly different between RA females and males. The expression quantitative trait loci (eQTL) analysis revealed a significant gender effect of the FoxP3 promoter polymorphism rs3761548A/C on miR-221, miR-222 and miR-532 expression levels, and of the FoxP3 polymorphism rs2232365A/G on miR-221 expression levels in PBMC of RA patients. These data further support the involvement of the X chromosome in RA susceptibility. X-linked miRNAs, in the context of sex differences, might provide novel insight into new molecular mechanisms and potential therapeutic targets in RA for disease treatment and prevention. Full article
Show Figures

Graphical abstract

4800 KiB  
Article
Upregulated MicroRNA-25 Mediates the Migration of Melanoma Cells by Targeting DKK3 through the WNT/β-Catenin Pathway
by Jia Huo, Yanfei Zhang, Ruilian Li, Yuan Wang, Jiawen Wu and Dingwei Zhang
Int. J. Mol. Sci. 2016, 17(11), 1124; https://doi.org/10.3390/ijms17111124 - 27 Oct 2016
Cited by 37 | Viewed by 5877
Abstract
Previous research indicates that microRNA-25 (miR-25) regulates carcinogenesis and the progression of various cancers, but the role of miR-25 in melanoma remains unclear. We observed that miR-25 was significantly upregulated in melanoma cell lines and tissue samples. Downregulation of miR-25 markedly suppressed invasion [...] Read more.
Previous research indicates that microRNA-25 (miR-25) regulates carcinogenesis and the progression of various cancers, but the role of miR-25 in melanoma remains unclear. We observed that miR-25 was significantly upregulated in melanoma cell lines and tissue samples. Downregulation of miR-25 markedly suppressed invasion and proliferation of melanoma cells in vitro; however, overexpression of miR-25 markedly increased melanoma cell invasion and proliferation. Moreover, we observed Dickkopf-related protein 3 (DKK3) as a direct target of miR-25 in vitro. Upregulation of DKK3 partially attenuated the oncogenic effect of miR-25 on melanoma cells. Ectopic expression of miR-25 in melanoma cells induced β-catenin accumulation in nuclear and inhibited TCF4 (T cell factor 4) activity, as well as the expression of c-Myc and Cyclin D1. In a nude xenograft model, miR-25 upregulation significantly increased A375 melanoma growth. In summary, miR-25 is upregulated in melanoma and promotes melanoma cell proliferation and invasion, partially by targeting DKK3. These results were indicated that miR-25 may serve as a potential target for the treatment of melanoma in the future. Full article
Show Figures

Graphical abstract

662 KiB  
Review
miR-155: A Novel Target in Allergic Asthma
by Hong Zhou, Junyao Li, Peng Gao, Qi Wang and Jie Zhang
Int. J. Mol. Sci. 2016, 17(10), 1773; https://doi.org/10.3390/ijms17101773 - 24 Oct 2016
Cited by 65 | Viewed by 6385
Abstract
MicroRNAs (miRNAs), a class of small non-coding RNAs of 18–24 nucleotides in length, function to posttranscriptionally regulate protein expression. miR-155 was one of the first identified and, to date, the most studied miRNA, and has been linked to various cellular processes such as [...] Read more.
MicroRNAs (miRNAs), a class of small non-coding RNAs of 18–24 nucleotides in length, function to posttranscriptionally regulate protein expression. miR-155 was one of the first identified and, to date, the most studied miRNA, and has been linked to various cellular processes such as modulation of immune responses and oncogenesis. Previous studies have identified miR-155 as a crucial positive regulator of Th1 immune response in autoimmune diseases, but as a suppressor of Th2 immunity in allergic disorders. However, recent studies have found new evidence that miR-155 plays an indispensible role in allergic asthma. This review summarizes the recent findings with respect to miR-155 in immune responses and the underlying mechanisms responsible for miR-155-related allergic diseases, as well as the similarities between miR-155 and glucocorticoids in immunity. Full article
Show Figures

Graphical abstract

1486 KiB  
Article
A Comprehensive MicroRNA Expression Profile of Liver and Lung Metastases of Colorectal Cancer with Their Corresponding Host Tissue and Its Prognostic Impact on Survival
by Mathieu Pecqueux, Isabell Liebetrau, Wiebke Werft, Hendrik Dienemann, Thomas Muley, Joachim Pfannschmidt, Benjamin Müssle, Nuh Rahbari, Sebastian Schölch, Markus W. Büchler, Jürgen Weitz, Christoph Reissfelder and Christoph Kahlert
Int. J. Mol. Sci. 2016, 17(10), 1755; https://doi.org/10.3390/ijms17101755 - 21 Oct 2016
Cited by 18 | Viewed by 6217
Abstract
MicroRNAs are small non-coding RNAs with a length of 18–25 nucleotides. They can regulate tumor invasion and metastasis by changing the expression and translation of their target mRNAs. Their expression is substantially altered in colorectal cancer cells as well as in the adjacent [...] Read more.
MicroRNAs are small non-coding RNAs with a length of 18–25 nucleotides. They can regulate tumor invasion and metastasis by changing the expression and translation of their target mRNAs. Their expression is substantially altered in colorectal cancer cells as well as in the adjacent tumor-associated stroma. Both of these compartments have a mutual influence on tumor progression. In the development of metastases, cancer cells initially interact with the host tissue. Therefore, compartment-specific expression signatures of these three locations—tumor, associated stroma, and host tissue—can provide new insights into the complex tumor biology of colorectal cancer. Frozen tissue samples of colorectal liver (n = 25) and lung metastases (n = 24) were laser microdissected to separate tumor cells and the adjacent tumor-associated stroma cells. Additionally, normal lung and liver tissue was collected from the same patients. We performed a microarray analysis in four randomly selected liver metastases and four randomly selected lung metastases, analyzing a total of 939 human miRNAs. miRNAs with a significant change >2-fold between the tumor, tumor stroma, and host tissue were analyzed in all samples using RT-qPCR (11 miRNAs) and correlated with the clinical data. We found a differential expression of several miRNAs between the tumor, the tumor-associated stroma, and the host tissue compartment. When comparing liver and lung metastases, miR-194 showed a 1.5-fold; miR-125, miR-127, and miR-192 showed a 2.5-fold; miR-19 and miR-215 a 3-fold; miR-145, miR-199-3, and miR-429 a 5-fold; miR-21 a 7-fold; and, finally, miR-199-5 a 12.5-fold downregulation in liver metastases compared to lung metastases. Furthermore miR-19, miR-125, miR-127, miR-192, miR-194, miR-199-5, and miR-215 showed a significant upregulation in the normal liver tissue compared to the normal lung tissue. Univariate analysis identified an association of poor survival with the expression of miR-125 (p = 0.05), miR-127 (p = 0.001), miR-145 (p = 0.005), miR-192 (p = 0.015), miR-194 (0.003), miR-199-5 (p = 0.008), miR-215 (p < 0.001), and miR-429 (p = 0.03) in the host liver tissue of the liver metastases. Colorectal liver and lung metastases have a unique miRNA expression profile. miRNA expression in the host tissue of colorectal liver metastases seems to be able to influence tumor progression and survival. These findings can be used in the development of tailored therapies. Full article
Show Figures

Figure 1

602 KiB  
Review
Regulatory Roles of MicroRNAs in Diabetes
by Juan Feng, Wanli Xing and Lan Xie
Int. J. Mol. Sci. 2016, 17(10), 1729; https://doi.org/10.3390/ijms17101729 - 17 Oct 2016
Cited by 115 | Viewed by 7740
Abstract
MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs in eukaryotes, have been recognized as significant regulators of gene expression through post-transcriptional mechanisms. To date, >2000 miRNAs have been identified in the human genome, and they orchestrate a variety of biological and pathological [...] Read more.
MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs in eukaryotes, have been recognized as significant regulators of gene expression through post-transcriptional mechanisms. To date, >2000 miRNAs have been identified in the human genome, and they orchestrate a variety of biological and pathological processes. Disruption of miRNA levels correlates with many diseases, including diabetes mellitus, a complex multifactorial metabolic disorder affecting >400 million people worldwide. miRNAs are involved in the pathogenesis of diabetes mellitus by affecting pancreatic β-cell functions, insulin resistance, or both. In this review, we summarize the investigations of the regulatory roles of important miRNAs in diabetes, as well as the potential of circulating miRNAs as diagnostic markers for diabetes mellitus. Full article
Show Figures

Graphical abstract

10930 KiB  
Article
MicroRNA-375 Functions as a Tumor-Suppressor Gene in Gastric Cancer by Targeting Recepteur d’Origine Nantais
by Sen Lian, Jung Sun Park, Yong Xia, Thi Thinh Nguyen, Young Eun Joo, Kyung Keun Kim, Hark Kyun Kim and Young Do Jung
Int. J. Mol. Sci. 2016, 17(10), 1633; https://doi.org/10.3390/ijms17101633 - 27 Sep 2016
Cited by 22 | Viewed by 5608
Abstract
Emerging evidence supports a fundamental role for microRNAs (miRNA) in regulating cancer metastasis. Recently, microRNA-375 (miR-375) was reported to be downregulated in many types of cancers, including gastric cancer. Increase in the expression of Recepteur d’Origine Nantais (RON), a receptor tyrosine [...] Read more.
Emerging evidence supports a fundamental role for microRNAs (miRNA) in regulating cancer metastasis. Recently, microRNA-375 (miR-375) was reported to be downregulated in many types of cancers, including gastric cancer. Increase in the expression of Recepteur d’Origine Nantais (RON), a receptor tyrosine kinase, has been reported in tumors. However, the function of miR-375 and RON expression in gastric cancer metastasis has not been sufficiently studied. In silico analysis identified miR-375 binding sites in the 3′-untranslated regions (3′-UTR) of the RON-encoding gene. Expression of miR-375 resulted in reduced activity of a luciferase reporter containing the 3′-UTR fragments of RON-encoding mRNA, confirming that miR-375 directly targets the 3′-UTR of RON mRNA. Moreover, we found that overexpression of miR-375 inhibited mRNA and protein expression of RON, which was accompanied by the suppression of cell proliferation, migration, and invasion in gastric cancer AGS and MKN-28 cells. Ectopic miR-375 expression also induced G1 cell cycle arrest through a decrease in the expression of cyclin D1, cyclin D3, and in the phosphorylation of retinoblastoma (Rb). Knockdown of RON by RNAi, similar to miR-375 overexpression, suppressed tumorigenic properties and induced G1 arrest through a decrease in the expression of cyclin D1, cyclin D3, and in the phosphorylation of Rb. Thus, our study provides evidence that miR-375 acts as a suppressor of metastasis in gastric cancer by targeting RON, and might represent a new potential therapeutic target for gastric cancer. Full article
Show Figures

Graphical abstract

1245 KiB  
Article
miR33a/miR33b* and miR122 as Possible Contributors to Hepatic Lipid Metabolism in Obese Women with Nonalcoholic Fatty Liver Disease
by Teresa Auguet, Gemma Aragonès, Alba Berlanga, Esther Guiu-Jurado, Andreu Martí, Salomé Martínez, Fàtima Sabench, Mercé Hernández, Carmen Aguilar, Joan Josep Sirvent, Daniel Del Castillo and Cristóbal Richart
Int. J. Mol. Sci. 2016, 17(10), 1620; https://doi.org/10.3390/ijms17101620 - 24 Sep 2016
Cited by 44 | Viewed by 5533
Abstract
Specific miRNA expression profiles have been shown to be associated with nonalcoholic fatty liver disease (NAFLD). We examined the correlation between the circulating levels and hepatic expression of miR122 and miR33a/b*, the key lipid metabolism-related gene expression and the clinicopathological factors of obese [...] Read more.
Specific miRNA expression profiles have been shown to be associated with nonalcoholic fatty liver disease (NAFLD). We examined the correlation between the circulating levels and hepatic expression of miR122 and miR33a/b*, the key lipid metabolism-related gene expression and the clinicopathological factors of obese women with NAFLD. We measured miR122 and miR33a/b* expression in liver samples from 62 morbidly obese (MO), 30 moderately obese (ModO), and eight normal-weight controls. MiR122 and miR33a/b* expression was analyzed by qRT-PCR. Additionally, miR122 and miR33b* circulating levels were analyzed in 122 women. Hepatic miR33b* expression was increased in MO compared to ModO and controls, whereas miR122 expression was decreased in the MO group compared to ModO. In obese cohorts, miR33b* expression was increased in nonalcoholic steatohepatitis (NASH). Regarding circulating levels, MO patients with NASH showed higher miR122 levels than MO with simple steatosis (SS). These circulating levels are good predictors of histological features associated with disease severity. MO is associated with altered hepatic miRNA expression. In obese women, higher miR33b* liver expression is associated with NASH. Moreover, multiple correlations between miRNAs and the expression of genes related to lipid metabolism were found, that would suggest a miRNA-host gene circuit. Finally, miR122 circulating levels could be included in a panel of different biomarkers to improve accuracy in the non-invasive diagnosis of NASH. Full article
Show Figures

Graphical abstract

4057 KiB  
Article
Long Noncoding RNA lncCAMTA1 Promotes Proliferation and Cancer Stem Cell-Like Properties of Liver Cancer by Inhibiting CAMTA1
by Li-Juan Ding, Yan Li, Shu-Dong Wang, Xin-Sen Wang, Fang Fang, Wei-Yao Wang, Peng Lv, Dong-Hai Zhao, Feng Wei and Ling Qi
Int. J. Mol. Sci. 2016, 17(10), 1617; https://doi.org/10.3390/ijms17101617 - 23 Sep 2016
Cited by 60 | Viewed by 6722
Abstract
Hepatocellular carcinoma (HCC) is the most common subtype of liver malignancy, and it is characterized by poor prognosis because of cancer stem cell (CSC)-mediated high postsurgical recurrence rates. Thus, targeting CSCs, or HCC cells with CSC-like properties, is an effective strategy for HCC [...] Read more.
Hepatocellular carcinoma (HCC) is the most common subtype of liver malignancy, and it is characterized by poor prognosis because of cancer stem cell (CSC)-mediated high postsurgical recurrence rates. Thus, targeting CSCs, or HCC cells with CSC-like properties, is an effective strategy for HCC therapy. Here, using long noncoding RNA (lncRNA) microarray analysis, we identified a novel lncRNA termed lncCAMTA1 that is increased in both liver CSCs and HCC. High lncCAMTA1 expression in HCC indicates poor clinical outcome. In vitro and in vivo functional experiments showed that overexpression of lncCAMTA1 promotes HCC cell proliferation, CSC-like properties, and tumorigenesis. Conversely, depletion of lncCAMTA1 inhibits HCC cell proliferation, CSC-like properties, and tumorigenesis. Mechanistically, we demonstrated that lncCAMTA1 physically associates with the calmodulin binding transcription activator 1 (CAMTA1) promoter, induces a repressive chromatin structure, and inhibits CAMTA1 transcription. Furthermore, CAMTA1 is required for the effects of lncCAMTA1 on HCC cell proliferation and CSC-like properties, and the expression of lncCAMTA1 and CAMTA1 is significantly negatively correlated in HCC tissues. Collectively, our study revealed the important roles and underlying molecular mechanisms of lncCAMTA1 on HCC, and suggested that lncCAMTA1 could be an effective prognostic factor and a potential therapeutic target for HCC. Full article
Show Figures

Figure 1

146 KiB  
Commentary
A MicroRNA that Regulates TLR-Mediated Fibrosis
by Laura Duffy and Steven O’Reilly
Int. J. Mol. Sci. 2016, 17(9), 1519; https://doi.org/10.3390/ijms17091519 - 09 Sep 2016
Cited by 1 | Viewed by 3637
Abstract
Hepatic damage can be caused by an array of factors which, if sustained, can lead to hepatic fibrosis.[...] Full article
275 KiB  
Review
Current Status of Long Non-Coding RNAs in Human Breast Cancer
by Stefanie Cerk, Daniela Schwarzenbacher, Jan Basri Adiprasito, Michael Stotz, Georg C. Hutterer, Armin Gerger, Hui Ling, George Adrian Calin and Martin Pichler
Int. J. Mol. Sci. 2016, 17(9), 1485; https://doi.org/10.3390/ijms17091485 - 06 Sep 2016
Cited by 60 | Viewed by 6302
Abstract
Breast cancer represents a major health burden in Europe and North America, as recently published data report breast cancer as the second leading cause of cancer related death in women worldwide. Breast cancer is regarded as a highly heterogeneous disease in terms of [...] Read more.
Breast cancer represents a major health burden in Europe and North America, as recently published data report breast cancer as the second leading cause of cancer related death in women worldwide. Breast cancer is regarded as a highly heterogeneous disease in terms of clinical course and biological behavior and can be divided into several molecular subtypes, with different prognosis and treatment responses. The discovery of numerous non-coding RNAs has dramatically changed our understanding of cell biology, especially the pathophysiology of cancer. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts >200 nucleotides in length. Several studies have demonstrated their role as key regulators of gene expression, cell biology and carcinogenesis. Deregulated expression levels of lncRNAs have been observed in various types of cancers including breast cancer. lncRNAs are involved in cancer initiation, progression, and metastases. In this review, we summarize the recent literature to highlight the current status of this class of long non-coding lncRNAs in breast cancer. Full article
8154 KiB  
Article
MicroRNA-378 Alleviates Cerebral Ischemic Injury by Negatively Regulating Apoptosis Executioner Caspase-3
by Nan Zhang, Jie Zhong, Song Han, Yun Li, Yanling Yin and Junfa Li
Int. J. Mol. Sci. 2016, 17(9), 1427; https://doi.org/10.3390/ijms17091427 - 02 Sep 2016
Cited by 40 | Viewed by 5386
Abstract
miRNAs have been linked to many human diseases, including ischemic stroke, and are being pursued as clinical diagnostics and therapeutic targets. Among the aberrantly expressed miRNAs in our previous report using large-scale microarray screening, the downregulation of miR-378 in the peri-infarct region of [...] Read more.
miRNAs have been linked to many human diseases, including ischemic stroke, and are being pursued as clinical diagnostics and therapeutic targets. Among the aberrantly expressed miRNAs in our previous report using large-scale microarray screening, the downregulation of miR-378 in the peri-infarct region of middle cerebral artery occluded (MCAO) mice can be reversed by hypoxic preconditioning (HPC). In this study, the role of miR-378 in the ischemic injury was further explored. We found that miR-378 levels significantly decreased in N2A cells following oxygen-glucose deprivation (OGD) treatment. Overexpression of miR-378 significantly enhanced cell viability, decreased TUNEL-positive cells and the immunoreactivity of cleaved-caspase-3. Conversely, downregulation of miR-378 aggravated OGD-induced apoptosis and ischemic injury. By using bioinformatic algorithms, we discovered that miR-378 may directly bind to the predicted 3′-untranslated region (UTR) of Caspase-3 gene. The protein level of caspase-3 increased significantly upon OGD treatment, and can be downregulated by pri-miR-378 transfection. The luciferase reporter assay confirmed the binding of miR-378 to the 3′-UTR of Caspase-3 mRNA and repressed its translation. In addition, miR-378 agomir decreased cleaved-caspase-3 ratio, reduced infarct volume and neural cell death induced by MCAO. Furthermore, caspase-3 knockdown could reverse anti-miR-378 mediated neuronal injury. Taken together, our data demonstrated that miR-378 attenuated ischemic injury by negatively regulating the apoptosis executioner, caspase-3, providing a potential therapeutic target for ischemic stroke. Full article
Show Figures

Graphical abstract

6125 KiB  
Article
A Long Noncoding RNA ZEB1-AS1 Promotes Tumorigenesis and Predicts Poor Prognosis in Glioma
by Qiao-Li Lv, Lei Hu, Shu-Hui Chen, Bao Sun, Meng-Long Fu, Chong-Zhen Qin, Qiang Qu, Gui-Hua Wang, Chen-Jie He and Hong-Hao Zhou
Int. J. Mol. Sci. 2016, 17(9), 1431; https://doi.org/10.3390/ijms17091431 - 30 Aug 2016
Cited by 90 | Viewed by 7671
Abstract
Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in [...] Read more.
Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in glioma tissues, being closely related to clinical stage of glioma. Moreover, patients with high ZEB1-AS1 levels had poor prognoses, with the evidence provided by multivariate Cox regression analysis indicating that ZEB1-AS1 expression could serve as an independent prognostic factor in glioma patients. Functionally, silencing of ZEB1-AS1 could significantly inhibit cell proliferation, migration, and invasion, as well as promote apoptosis. Knockdown of ZEB1-AS1 significantly induced the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells. Further analysis indicated that ZEB1-AS1 could regulate the cell cycle by inhibiting the expression of G1/S transition key regulators, such as Cyclin D1 and CDK2. Furthermore, ZEB1-AS1 functioned as an important regulator of migration and invasion via activating epithelial to mesenchymal transition (EMT) through up-regulating the expression of ZEB1, MMP2, MMP9, N-cadherin, and Integrin-β1 as well as decreasing E-cadherin levels in the metastatic progression of glioma. Additionally, forced down-regulation of ZEB1-AS1 could dramatically promote apoptosis by increasing the expression level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggest that ZEB1-AS1 may serve as a new prognostic biomarker and therapeutic target of glioma. Full article
Show Figures

Graphical abstract

6891 KiB  
Article
MicroRNA-381 Regulates Chondrocyte Hypertrophy by Inhibiting Histone Deacetylase 4 Expression
by Weishen Chen, Puyi Sheng, Zhiyu Huang, Fangang Meng, Yan Kang, Guangxin Huang, Zhiqi Zhang, Weiming Liao and Ziji Zhang
Int. J. Mol. Sci. 2016, 17(9), 1377; https://doi.org/10.3390/ijms17091377 - 23 Aug 2016
Cited by 37 | Viewed by 5630
Abstract
Chondrocyte hypertrophy, regulated by Runt-related transcription factor 2 (RUNX2) and matrix metalloproteinase 13 (MMP13), is a crucial step in cartilage degeneration and osteoarthritis (OA) pathogenesis. We previously demonstrated that microRNA-381 (miR-381) promotes MMP13 expression during chondrogenesis and contributes to cartilage degeneration; however, the [...] Read more.
Chondrocyte hypertrophy, regulated by Runt-related transcription factor 2 (RUNX2) and matrix metalloproteinase 13 (MMP13), is a crucial step in cartilage degeneration and osteoarthritis (OA) pathogenesis. We previously demonstrated that microRNA-381 (miR-381) promotes MMP13 expression during chondrogenesis and contributes to cartilage degeneration; however, the mechanism underlying this process remained unclear. In this study, we observed divergent expression of miR-381 and histone deacetylase 4 (HDAC4), an enzyme that directly inhibits RUNX2 and MMP13 expression, during late-stage chondrogenesis of ATDC5 cells, as well as in prehypertrophic and hypertrophic chondrocytes during long bone development in E16.5 mouse embryos. We therefore investigated whether this miRNA regulates HDAC4 expression during chondrogenesis. Notably, overexpression of miR-381 inhibited HDAC4 expression but promoted RUNX2 expression. Moreover, transfection of SW1353 cells with an miR-381 mimic suppressed the activity of a reporter construct containing the 3′-untranslated region (3′-UTR) of HDAC4. Conversely, treatment with a miR-381 inhibitor yielded increased HDAC4 expression and decreased RUNX2 expression. Lastly, knockdown of HDAC4 expression resulted in increased RUNX2 and MMP13 expression in SW1353 cells. Collectively, our results indicate that miR-381 epigenetically regulates MMP13 and RUNX2 expression via targeting of HDAC4, thereby suggesting the possibilities of inhibiting miR-381 to control chondrocyte hypertrophy and cartilage degeneration. Full article
Show Figures

Graphical abstract

726 KiB  
Article
Plasma LncRNA-ATB, a Potential Biomarker for Diagnosis of Patients with Coal Workers’ Pneumoconiosis: A Case-Control Study
by Jixuan Ma, Xiuqing Cui, Yi Rong, Yun Zhou, Yanjun Guo, Min Zhou, Lili Xiao and Weihong Chen
Int. J. Mol. Sci. 2016, 17(8), 1367; https://doi.org/10.3390/ijms17081367 - 22 Aug 2016
Cited by 19 | Viewed by 6007
Abstract
LncRNA-ATB (lncRNA was activated by transforming growth factor-β) has been reported to be involved in specific physiological and pathological processes in human diseases, and could serve as biomarkers for cancers. However, the role of lncRNA-ATB in coal workers’ pneumoconiosis (CWP) is still unknown. [...] Read more.
LncRNA-ATB (lncRNA was activated by transforming growth factor-β) has been reported to be involved in specific physiological and pathological processes in human diseases, and could serve as biomarkers for cancers. However, the role of lncRNA-ATB in coal workers’ pneumoconiosis (CWP) is still unknown. This study aimed to investigate the association between lncRNA-ATB and CWP. Quantitative real-time polymerase chain reaction was performed to detect plasma lncRNA-ATB expression in 137 CWP patients, 72 healthy coal miners and 168 healthy controls. LncRNA-ATB was significantly upregulated in CWP (p < 0.05). Compared with the healthy controls and healthy coal miners, the odds ratios (ORs) (95% confidence interval (CI)) for CWP were 2.57 (1.52–4.33) and 2.17 (1.04–4.53), respectively. LncRNA-ATB was positively associated with transforming growth factor-β1 (TGF-β1) (r = 0.30, p = 0.003) and negative correlated with vital capacity (VC) (r = −0.18, p = 0.033) and forced vital capacity (FVC) (r = −0.18, p = 0.046) in CWP patients. Compared with healthy controls, the area under the curve (AUC) was 0.84, resulting in a 71.17% sensitivity and 88.14% specificity. When compared with healthy coal miners, the AUC was 0.83, the sensitivity and specificity were 70.07% and 86.36%, respectively. LncRNA-ATB expression is commonly increased in CWP and significantly correlates with the TGF-β1 in CWP patients. Furthermore, elevated lncRNA-ATB was associated with CWP risk and may serve as a potential biomarker for CWP. Full article
Show Figures

Graphical abstract

3838 KiB  
Communication
SMA Human iPSC-Derived Motor Neurons Show Perturbed Differentiation and Reduced miR-335-5p Expression
by Michela Murdocca, Silvia Anna Ciafrè, Paola Spitalieri, Rosa Valentina Talarico, Massimo Sanchez, Giuseppe Novelli and Federica Sangiuolo
Int. J. Mol. Sci. 2016, 17(8), 1231; https://doi.org/10.3390/ijms17081231 - 30 Jul 2016
Cited by 20 | Viewed by 6160
Abstract
Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival Motor Neuron 1 gene, resulting in very low levels of functional Survival of Motor Neuron (SMN) protein. SMA human induced Pluripotent Stem Cells (hiPSCs) represent a useful and valid [...] Read more.
Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival Motor Neuron 1 gene, resulting in very low levels of functional Survival of Motor Neuron (SMN) protein. SMA human induced Pluripotent Stem Cells (hiPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. MicroRNAs (miRNAs) are often reported as playing a key role in regulating neuronal differentiation and fate specification. In this study SMA hiPSCs have been differentiated towards early motor neurons and their molecular and immunocytochemical profile were compared to those of wild type cells. Cell cycle proliferation was also evaluated by fluorescence-activated cell sorting (FACS). SMA hiPSCs showed an increased proliferation rate and also higher levels of stem cell markers. Moreover; when differentiated towards early motor neurons they expressed lower levels of NCAM and MN specific markers. The expression of miR-335-5p; already identified to control self-renewal or differentiation of mouse embryonic stem cells (mESCs); resulted to be reduced during the early steps of differentiation of SMA hiPSCs compared to wild type cells. These results suggest that we should speculate a role of this miRNA both in stemness characteristic and in differentiation efficiency of these cells. Full article
Show Figures

Figure 1

4516 KiB  
Article
MicroRNA-146a-5p Negatively Regulates Pro-Inflammatory Cytokine Secretion and Cell Activation in Lipopolysaccharide Stimulated Human Hepatic Stellate Cells through Inhibition of Toll-Like Receptor 4 Signaling Pathways
by Yuhan Chen, Zhaochong Zeng, Xiaoyun Shen, Zhifeng Wu, Yinying Dong and Jason Chia-Hsien Cheng
Int. J. Mol. Sci. 2016, 17(7), 1076; https://doi.org/10.3390/ijms17071076 - 07 Jul 2016
Cited by 56 | Viewed by 7245
Abstract
Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this [...] Read more.
Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB). Knockdown of IRAK1 and TRAF6 also suppressed pro-inflammatory cytokine production by inhibiting NF-κB phosphorylation. In addition, miR-146a-5p mimic blocked LPS induced TRAF6 dependent c-Jun N-terminal kinase (JNK) and Smad2 activation as well as α-SMA production. Taken together, these results suggest that miR-146a-5p suppresses pro-inflammatory cytokine secretion and cell activation of HSC through inhibition of TLR4/NF-κB and TLR4/TRAF6/JNK pathway. Full article
Show Figures

Graphical abstract

5332 KiB  
Article
miR-218 Involvement in Cardiomyocyte Hypertrophy Is Likely through Targeting REST
by Jing-Jing Liu, Cui-Mei Zhao, Zhi-Gang Li, Yu-Mei Wang, Wei Miao, Xiu-Juan Wu, Wen-Jing Wang, Chang Liu, Duo Wang, Kang Wang, Li Li and Lu-Ying Peng
Int. J. Mol. Sci. 2016, 17(6), 848; https://doi.org/10.3390/ijms17060848 - 31 May 2016
Cited by 18 | Viewed by 5689
Abstract
MicroRNAs (miRNAs) have been identified as key players in cardiomyocyte hypertrophy, which is associated with significant risks of heart failure. However, many microRNAs are still not recognized for their functions in pathophysiological processes. In this study, we evaluated effects of miR-218 in cardiomyocyte [...] Read more.
MicroRNAs (miRNAs) have been identified as key players in cardiomyocyte hypertrophy, which is associated with significant risks of heart failure. However, many microRNAs are still not recognized for their functions in pathophysiological processes. In this study, we evaluated effects of miR-218 in cardiomyocyte hypertrophy using both in vitro and in vivo models. We found that miR-218 was evidently downregulated in a transverse aortic constriction (TAC) mouse model. Overexpression of miR-218 is sufficient to reduce hypertrophy, whereas the suppression of miR-218 aggravates hypertrophy in primary cardiomyocytes induced by isoprenaline (ISO). In addition, we identified RE1-silencing transcription factor (REST) as a novel target of miR-218; it negatively regulated the expression of REST in hypertrophic cardiomyocytes and the TAC model. These results showed that miR-218 plays a crucial role in cardiomyocyte hypertrophy, likely via targeting REST, suggesting a potential candidate target for interfering hypertrophy. Full article
Show Figures

Graphical abstract

3451 KiB  
Review
Understanding the Functions of Long Non-Coding RNAs through Their Higher-Order Structures
by Rui Li, Hongliang Zhu and Yunbo Luo
Int. J. Mol. Sci. 2016, 17(5), 702; https://doi.org/10.3390/ijms17050702 - 17 May 2016
Cited by 80 | Viewed by 9888
Abstract
Although thousands of long non-coding RNAs (lncRNAs) have been discovered in eukaryotes, very few molecular mechanisms have been characterized due to an insufficient understanding of lncRNA structure. Therefore, investigations of lncRNA structure and subsequent elucidation of the regulatory mechanisms are urgently needed. However, [...] Read more.
Although thousands of long non-coding RNAs (lncRNAs) have been discovered in eukaryotes, very few molecular mechanisms have been characterized due to an insufficient understanding of lncRNA structure. Therefore, investigations of lncRNA structure and subsequent elucidation of the regulatory mechanisms are urgently needed. However, since lncRNA are high molecular weight molecules, which makes their crystallization difficult, obtaining information about their structure is extremely challenging, and the structures of only several lncRNAs have been determined so far. Here, we review the structure–function relationships of the widely studied lncRNAs found in the animal and plant kingdoms, focusing on the principles and applications of both in vitro and in vivo technologies for the study of RNA structures, including dimethyl sulfate-sequencing (DMS-seq), selective 2′-hydroxyl acylation analyzed by primer extension-sequencing (SHAPE-seq), parallel analysis of RNA structure (PARS), and fragmentation sequencing (FragSeq). The aim of this review is to provide a better understanding of lncRNA biological functions by studying them at the structural level. Full article
Show Figures

Graphical abstract

400 KiB  
Review
Expression and Function of miR-155 in Diseases of the Gastrointestinal Tract
by Jianhua Wan, Liang Xia, Wenting Xu and Nonghua Lu
Int. J. Mol. Sci. 2016, 17(5), 709; https://doi.org/10.3390/ijms17050709 - 11 May 2016
Cited by 46 | Viewed by 5450
Abstract
MicroRNAs (miRNAs) are a type of small noncoding RNA that can regulate the expression of target genes under physiological and pathophysiological conditions. miR-155 is a multifunctional miRNA with inflammation-related and oncogenic roles. In particular, the dysregulation of miR-155 has been strongly implicated in [...] Read more.
MicroRNAs (miRNAs) are a type of small noncoding RNA that can regulate the expression of target genes under physiological and pathophysiological conditions. miR-155 is a multifunctional miRNA with inflammation-related and oncogenic roles. In particular, the dysregulation of miR-155 has been strongly implicated in Helicobacter pylori-related gastric disease, inflammatory bowel disease, and colorectal cancer in addition to being involved in molecular changes of important targets and signaling pathways. This review focuses on the expression and function of miR-155 during inflammation and carcinogenesis and its potential use as an effective therapeutic target for certain gastrointestinal diseases. Full article
Show Figures

Graphical abstract

5758 KiB  
Article
Mmu-miR-1894-3p Inhibits Cell Proliferation and Migration of Breast Cancer Cells by Targeting Trim46
by Li Zhang, Xiaoying Li, Wei Dong, Caixian Sun, Deyu Guo and Lianfeng Zhang
Int. J. Mol. Sci. 2016, 17(4), 609; https://doi.org/10.3390/ijms17040609 - 22 Apr 2016
Cited by 24 | Viewed by 10114
Abstract
Breast cancer is the second leading cause of cancer death in women and the presence of metastasis significantly decreases survival. MicroRNAs are involved in tumor progression and the metastatic spreading of breast cancer. Here, we reported that a microRNA, mmu-miR-1894, significantly decreased the [...] Read more.
Breast cancer is the second leading cause of cancer death in women and the presence of metastasis significantly decreases survival. MicroRNAs are involved in tumor progression and the metastatic spreading of breast cancer. Here, we reported that a microRNA, mmu-miR-1894, significantly decreased the lung metastasis of 4TO7 mouse breast cancer cells by 86.7% in mouse models. Mmu-miR-1894-3p was the functional mature form of miR-1894 and significantly decreased the lung metastasis of 4TO7 cells by 90.8% in mouse models. A dual-luciferase reporter assay indicated that mmu-miR-1894-3p directly targeted the tripartite motif containing 46 (Trim46) 3′-untranslated region (UTR) and downregulated the expression of Trim46 in 4TO7 cells. Consistent with the effect of mmu-miR-1894-3p, knockdown of Trim46 inhibited the experimental lung metastasis of 4TO7 cells. Moreover, knockdown of human Trim46 also prohibited the cell proliferation, migration and wound healing of MBA-MD-231 human breast cancer cells. These results suggested that the effect of knockdown of Trim46 alone was sufficient to recapitulate the effect of mmu-miR-1894 on the metastasis of the breast cancer cells in mouse and that Trim46 was involved in the proliferation and migration of mouse and human breast cancer cells. Full article
Show Figures

Graphical abstract

417 KiB  
Editorial
Non-Coding RNAs in Cancer: An Interview with Dr. Martin Pichler
by International Journal of Molecular Sciences Editorial Office
Int. J. Mol. Sci. 2016, 17(4), 605; https://doi.org/10.3390/ijms17040605 - 21 Apr 2016
Cited by 14 | Viewed by 5098
Abstract
In this issue, we are pleased and honored to have an interview with Professor Martin Pichler, who is the Collection Editor for the International Journal of Molecular Sciences Topical Collection of “Regulation by Non-Coding RNAs” [1].[...] Full article
705 KiB  
Review
Current Insights into Long Non-Coding RNAs in Renal Cell Carcinoma
by Maximilian Seles, Georg C. Hutterer, Tobias Kiesslich, Karl Pummer, Ioana Berindan-Neagoe, Samantha Perakis, Daniela Schwarzenbacher, Michael Stotz, Armin Gerger and Martin Pichler
Int. J. Mol. Sci. 2016, 17(4), 573; https://doi.org/10.3390/ijms17040573 - 15 Apr 2016
Cited by 71 | Viewed by 6733
Abstract
Renal cell carcinoma (RCC) represents a deadly disease with rising mortality despite intensive therapeutic efforts. It comprises several subtypes in terms of distinct histopathological features and different clinical presentations. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts in the genome which vary in expression [...] Read more.
Renal cell carcinoma (RCC) represents a deadly disease with rising mortality despite intensive therapeutic efforts. It comprises several subtypes in terms of distinct histopathological features and different clinical presentations. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts in the genome which vary in expression levels and length and perform diverse functions. They are involved in the inititation, evolution and progression of primary cancer, as well as in the development and spread of metastases. Recently, several lncRNAs were described in RCC. This review emphasises the rising importance of lncRNAs in RCC. Moreover, it provides an outlook on their therapeutic potential in the future. Full article
Show Figures

Figure 1

4949 KiB  
Article
Inhibition of IFN-γ-Induced Nitric Oxide Dependent Antimycobacterial Activity by miR-155 and C/EBPβ
by Yongwei Qin, Qinglan Wang, Youlang Zhou, Yinong Duan and Qian Gao
Int. J. Mol. Sci. 2016, 17(4), 535; https://doi.org/10.3390/ijms17040535 - 08 Apr 2016
Cited by 28 | Viewed by 6302
Abstract
miR-155 (microRNA-155) is an important non-coding RNA in regulating host crucial biological regulators. However, its regulatory function in mycobacterium infection remains unclear. Our study demonstrates that miR-155 expression is significantly increased in macrophages after Mycobacterium marinum (M.m) infection. Transfection with anti-miR-155 [...] Read more.
miR-155 (microRNA-155) is an important non-coding RNA in regulating host crucial biological regulators. However, its regulatory function in mycobacterium infection remains unclear. Our study demonstrates that miR-155 expression is significantly increased in macrophages after Mycobacterium marinum (M.m) infection. Transfection with anti-miR-155 enhances nitric oxide (NO) synthesis and decreases the mycobacterium burden, and vice versa, in interferon γ (IFN-γ) activated macrophages. More importantly, miR-155 can directly bind to the 3′UTR of CCAAT/enhancer binding protein β (C/EBPβ), a positive transcriptional regulator of nitric oxide synthase (NOS2), and regulate C/EBPβ expression negatively. Knockdown of C/EBPβ inhibit the production of nitric oxide synthase and promoted mycobacterium survival. Collectively, these data suggest that M.m-induced upregulation of miR-155 downregulated the expression of C/EBPβ, thus decreasing the production of NO and promoting mycobacterium survival, which may provide an insight into the function of miRNA in subverting the host innate immune response by using mycobacterium for its own profit. Understanding how miRNAs partly regulate microbicidal mechanisms may represent an attractive way to control tuberculosis infectious. Full article
Show Figures

Graphical abstract

217 KiB  
Review
Novel Insights into the Role of Long Noncoding RNA in Ocular Diseases
by Fang Li, Xuyang Wen, He Zhang and Xianqun Fan
Int. J. Mol. Sci. 2016, 17(4), 478; https://doi.org/10.3390/ijms17040478 - 31 Mar 2016
Cited by 60 | Viewed by 8942
Abstract
Recent advances have suggested that long noncoding RNAs (lncRNAs) are differentially expressed in ocular tissues and play a critical role in the pathogenesis of different types of eye diseases. Here, we summarize the functions and mechanisms of known aberrantly-expressed lncRNAs and present a [...] Read more.
Recent advances have suggested that long noncoding RNAs (lncRNAs) are differentially expressed in ocular tissues and play a critical role in the pathogenesis of different types of eye diseases. Here, we summarize the functions and mechanisms of known aberrantly-expressed lncRNAs and present a brief overview of relevant reports about lncRNAs in such ocular diseases as glaucoma, proliferative vitreoretinopathy (PVR), diabeticretinopathy (DR), and ocular tumors. We intend to highlight comprehensive studies that provide detailed data about the mechanisms of lncRNAs, their applications as diagnostic or prognostic biomarkers, and their potential therapeutic targets. Although our understanding of lncRNAs is still in its infancy, these examples may provide helpful insights into the methods by which lncRNAs interfere with ocular diseases. Full article
Show Figures

Graphical abstract

1118 KiB  
Review
Crosstalk between Long Noncoding RNAs and MicroRNAs in Health and Disease
by Ahmed S. Bayoumi, Amer Sayed, Zuzana Broskova, Jian-Peng Teoh, James Wilson, Huabo Su, Yao-Liang Tang and Il-man Kim
Int. J. Mol. Sci. 2016, 17(3), 356; https://doi.org/10.3390/ijms17030356 - 11 Mar 2016
Cited by 199 | Viewed by 9417
Abstract
Protein-coding genes account for only a small part of the human genome; in fact, the vast majority of transcripts are comprised of non-coding RNAs (ncRNAs) including long ncRNAs (lncRNAs) and small ncRNAs, microRNAs (miRs). Accumulating evidence indicates that ncRNAs could play critical roles [...] Read more.
Protein-coding genes account for only a small part of the human genome; in fact, the vast majority of transcripts are comprised of non-coding RNAs (ncRNAs) including long ncRNAs (lncRNAs) and small ncRNAs, microRNAs (miRs). Accumulating evidence indicates that ncRNAs could play critical roles in regulating many cellular processes which are often implicated in health and disease. For example, ncRNAs are aberrantly expressed in cancers, heart diseases, and many other diseases. LncRNAs and miRs are therefore novel and promising targets to be developed into biomarkers for diagnosis and prognosis as well as treatment options. The interaction between lncRNAs and miRs as well as its pathophysiological significance have recently been reported. Mechanistically, it is believed that lncRNAs exert “sponge-like” effects on various miRs, which subsequently inhibits miR-mediated functions. This crosstalk between two types of ncRNAs frequently contributes to the pathogenesis of the disease. In this review, we provide a summary of the recent studies highlighting the interaction between these ncRNAs and the effects of this interaction on disease pathogenesis and regulation. Full article
Show Figures

Graphical abstract

552 KiB  
Article
miR-16-5p Is a Stably-Expressed Housekeeping MicroRNA in Breast Cancer Tissues from Primary Tumors and from Metastatic Sites
by Gabriel Rinnerthaler, Hubert Hackl, Simon Peter Gampenrieder, Frank Hamacher, Clemens Hufnagl, Cornelia Hauser-Kronberger, Franz Zehentmayr, Gerd Fastner, Felix Sedlmayer, Brigitte Mlineritsch and Richard Greil
Int. J. Mol. Sci. 2016, 17(2), 156; https://doi.org/10.3390/ijms17020156 - 26 Jan 2016
Cited by 63 | Viewed by 10002
Abstract
For quantitative microRNA analyses in formalin-fixed paraffin-embedded (FFPE) tissue, expression levels have to be normalized to endogenous controls. To investigate the most stably-expressed microRNAs in breast cancer and its surrounding tissue, we used tumor samples from primary tumors and from metastatic sites. MiRNA [...] Read more.
For quantitative microRNA analyses in formalin-fixed paraffin-embedded (FFPE) tissue, expression levels have to be normalized to endogenous controls. To investigate the most stably-expressed microRNAs in breast cancer and its surrounding tissue, we used tumor samples from primary tumors and from metastatic sites. MiRNA profiling using TaqMan® Array Human MicroRNA Cards, enabling quantification of 754 unique human miRNAs, was performed in FFPE specimens from 58 patients with metastatic breast cancer. Forty-two (72%) samples were collected from primary tumors and 16 (28%) from metastases. In a cross-platform analysis of a validation cohort of 32 FFPE samples from patients with early breast cancer genome-wide microRNA expression analysis using SurePrintG3 miRNA (8 × 60 K)® microarrays from Agilent® was performed. Eleven microRNAs could be detected in all samples analyzed. Based on NormFinder and geNorm stability values and the high correlation (rho ≥ 0.8) with the median of all measured microRNAs, miR-16-5p, miR-29a-3p, miR-126-3p, and miR-222-3p are suitable single gene housekeeper candidates. In the cross-platform validation, 29 human microRNAs were strongly expressed (mean log2-intensity > 10) and 21 of these microRNAs including miR-16-5p and miR-29a-3p were also stably expressed (CV < 5%). Thus, miR-16-5p and miR-29a-3p are both strong housekeeper candidates. Their Normfinder stability values calculated across the primary tumor and metastases subgroup indicate that miR-29a-3p can be considered as the strongest housekeeper in a cohort with mainly samples from primary tumors, whereas miR-16-5p might perform better in a metastatic sample enriched cohort. Full article
Show Figures

Graphical abstract

818 KiB  
Review
Structure Prediction: New Insights into Decrypting Long Noncoding RNAs
by Kun Yan, Yasir Arfat, Dijie Li, Fan Zhao, Zhihao Chen, Chong Yin, Yulong Sun, Lifang Hu, Tuanmin Yang and Airong Qian
Int. J. Mol. Sci. 2016, 17(1), 132; https://doi.org/10.3390/ijms17010132 - 21 Jan 2016
Cited by 49 | Viewed by 7808
Abstract
Long noncoding RNAs (lncRNAs), which form a diverse class of RNAs, remain the least understood type of noncoding RNAs in terms of their nature and identification. Emerging evidence has revealed that a small number of newly discovered lncRNAs perform important and complex biological [...] Read more.
Long noncoding RNAs (lncRNAs), which form a diverse class of RNAs, remain the least understood type of noncoding RNAs in terms of their nature and identification. Emerging evidence has revealed that a small number of newly discovered lncRNAs perform important and complex biological functions such as dosage compensation, chromatin regulation, genomic imprinting, and nuclear organization. However, understanding the wide range of functions of lncRNAs related to various processes of cellular networks remains a great experimental challenge. Structural versatility is critical for RNAs to perform various functions and provides new insights into probing the functions of lncRNAs. In recent years, the computational method of RNA structure prediction has been developed to analyze the structure of lncRNAs. This novel methodology has provided basic but indispensable information for the rapid, large-scale and in-depth research of lncRNAs. This review focuses on mainstream RNA structure prediction methods at the secondary and tertiary levels to offer an additional approach to investigating the functions of lncRNAs. Full article
Show Figures

Graphical abstract

1368 KiB  
Article
MiRNA-Target Interaction Reveals Cell-Specific Post-Transcriptional Regulation in Mammalian Cell Lines
by Varun Kulkarni, Afsar Raza Naqvi, Juhi Raju Uttamani and Salvador Nares
Int. J. Mol. Sci. 2016, 17(1), 72; https://doi.org/10.3390/ijms17010072 - 08 Jan 2016
Cited by 21 | Viewed by 4993
Abstract
MicroRNAs are 18–22 nucleotides long, non-coding RNAs that bind transcripts with complementary sequences leading to either mRNA degradation or translational suppression. However, the inherent differences in preferred mode of miRNA regulation among cells of different origin have not been examined. In our previous [...] Read more.
MicroRNAs are 18–22 nucleotides long, non-coding RNAs that bind transcripts with complementary sequences leading to either mRNA degradation or translational suppression. However, the inherent differences in preferred mode of miRNA regulation among cells of different origin have not been examined. In our previous transcriptome profiling studies, we observed that post-transcriptional regulation can differ substantially depending on the cell in context. Here we examined mechanistic differences in the regulation of a let-7a targeted (wild type) or resistant (mutant) engineered renilla transcript across various mammalian cell lines of diverse origin. Dual luciferase assays show that compared to mutant (mut), the reporter gene containing wild type (wt) let-7a binding sites was efficiently suppressed upon transfection in various cell lines. Importantly, the strength of miRNA regulation varied across the cell lines. Total RNA analysis demonstrates that wt renilla mRNA was expressed to similar or higher levels compared to mut suggesting that translation repression is a predominant mode of miRNA regulation. Nonetheless, transcript degradation was observed in some cell lines. Ago-2 immunoprecipitation show that miRNA repressed renilla mRNA are associated with functional mi-RISC (miRNA-RNA induced silencing complex). Given the immense potential of miRNA as a therapeutic option, these findings highlight the necessity to thoroughly examine the mode of mRNA regulation in order to achieve the beneficial effects in targeting cells. Full article
Show Figures

Graphical abstract

2015

Jump to: 2023, 2022, 2021, 2020, 2019, 2018, 2017, 2016, 2014

3405 KiB  
Article
Novel Insights into Guide RNA 5′-Nucleoside/Tide Binding by Human Argonaute 2
by Munishikha Kalia, Sarah Willkomm, Jens Christian Claussen, Tobias Restle and Alexandre M. J. J. Bonvin
Int. J. Mol. Sci. 2016, 17(1), 22; https://doi.org/10.3390/ijms17010022 - 24 Dec 2015
Cited by 7 | Viewed by 5601
Abstract
The human Argonaute 2 (hAgo2) protein is a key player of RNA interference (RNAi). Upon complex formation with small non-coding RNAs, the protein initially interacts with the 5′-end of a given guide RNA through multiple interactions within the MID domain. This interaction has [...] Read more.
The human Argonaute 2 (hAgo2) protein is a key player of RNA interference (RNAi). Upon complex formation with small non-coding RNAs, the protein initially interacts with the 5′-end of a given guide RNA through multiple interactions within the MID domain. This interaction has been reported to show a strong bias for U and A over C and G at the 5′-position. Performing molecular dynamics simulations of binary hAgo2/OH–guide–RNA complexes, we show that hAgo2 is a highly flexible protein capable of binding to guide strands with all four possible 5′-bases. Especially, in the case of C and G this is associated with rather large individual conformational rearrangements affecting the MID, PAZ and even the N-terminal domains to different degrees. Moreover, a 5′-G induces domain motions in the protein, which trigger a previously unreported interaction between the 5′-base and the L2 linker domain. Combining our in silico analyses with biochemical studies of recombinant hAgo2, we find that, contrary to previous observations, hAgo2 is capable of functionally accommodating guide strands regardless of the 5′-base. Full article
Show Figures

Graphical abstract

4753 KiB  
Article
MicroRNA-Target Network Inference and Local Network Enrichment Analysis Identify Two microRNA Clusters with Distinct Functions in Head and Neck Squamous Cell Carcinoma
by Steffen Sass, Adriana Pitea, Kristian Unger, Julia Hess, Nikola S. Mueller and Fabian J. Theis
Int. J. Mol. Sci. 2015, 16(12), 30204-30222; https://doi.org/10.3390/ijms161226230 - 18 Dec 2015
Cited by 11 | Viewed by 8206
Abstract
MicroRNAs represent ~22 nt long endogenous small RNA molecules that have been experimentally shown to regulate gene expression post-transcriptionally. One main interest in miRNA research is the investigation of their functional roles, which can typically be accomplished by identification of mi-/mRNA interactions and [...] Read more.
MicroRNAs represent ~22 nt long endogenous small RNA molecules that have been experimentally shown to regulate gene expression post-transcriptionally. One main interest in miRNA research is the investigation of their functional roles, which can typically be accomplished by identification of mi-/mRNA interactions and functional annotation of target gene sets. We here present a novel method “miRlastic”, which infers miRNA-target interactions using transcriptomic data as well as prior knowledge and performs functional annotation of target genes by exploiting the local structure of the inferred network. For the network inference, we applied linear regression modeling with elastic net regularization on matched microRNA and messenger RNA expression profiling data to perform feature selection on prior knowledge from sequence-based target prediction resources. The novelty of miRlastic inference originates in predicting data-driven intra-transcriptome regulatory relationships through feature selection. With synthetic data, we showed that miRlastic outperformed commonly used methods and was suitable even for low sample sizes. To gain insight into the functional role of miRNAs and to determine joint functional properties of miRNA clusters, we introduced a local enrichment analysis procedure. The principle of this procedure lies in identifying regions of high functional similarity by evaluating the shortest paths between genes in the network. We can finally assign functional roles to the miRNAs by taking their regulatory relationships into account. We thoroughly evaluated miRlastic on a cohort of head and neck cancer (HNSCC) patients provided by The Cancer Genome Atlas. We inferred an mi-/mRNA regulatory network for human papilloma virus (HPV)-associated miRNAs in HNSCC. The resulting network best enriched for experimentally validated miRNA-target interaction, when compared to common methods. Finally, the local enrichment step identified two functional clusters of miRNAs that were predicted to mediate HPV-associated dysregulation in HNSCC. Our novel approach was able to characterize distinct pathway regulations from matched miRNA and mRNA data. An R package of miRlastic was made available through: http://icb.helmholtz-muenchen.de/mirlastic. Full article
Show Figures

Graphical abstract

2322 KiB  
Review
The Mechanisms of Virulence Regulation by Small Noncoding RNAs in Low GC Gram-Positive Pathogens
by Stephanie Pitman and Kyu Hong Cho
Int. J. Mol. Sci. 2015, 16(12), 29797-29814; https://doi.org/10.3390/ijms161226194 - 14 Dec 2015
Cited by 14 | Viewed by 7528
Abstract
The discovery of small noncoding regulatory RNAs (sRNAs) in bacteria has grown tremendously recently, giving new insights into gene regulation. The implementation of computational analysis and RNA sequencing has provided new tools to discover and analyze potential sRNAs. Small regulatory RNAs that act [...] Read more.
The discovery of small noncoding regulatory RNAs (sRNAs) in bacteria has grown tremendously recently, giving new insights into gene regulation. The implementation of computational analysis and RNA sequencing has provided new tools to discover and analyze potential sRNAs. Small regulatory RNAs that act by base-pairing to target mRNAs have been found to be ubiquitous and are the most abundant class of post-transcriptional regulators in bacteria. The majority of sRNA studies has been limited to E. coli and other gram-negative bacteria. However, examples of sRNAs in gram-positive bacteria are still plentiful although the detailed gene regulation mechanisms behind them are not as well understood. Strict virulence control is critical for a pathogen’s survival and many sRNAs have been found to be involved in that process. This review outlines the targets and currently known mechanisms of trans-acting sRNAs involved in virulence regulation in various gram-positive pathogens. In addition, their shared characteristics such as CU interaction motifs, the role of Hfq, and involvement in two-component regulators, riboswitches, quorum sensing, or toxin/antitoxin systems are described. Full article
Show Figures

Figure 1

871 KiB  
Review
Tumor-Associated CSF MicroRNAs for the Prediction and Evaluation of CNS Malignancies
by Tarek Shalaby and Michael A. Grotzer
Int. J. Mol. Sci. 2015, 16(12), 29103-29119; https://doi.org/10.3390/ijms161226150 - 07 Dec 2015
Cited by 34 | Viewed by 6554
Abstract
Cerebrospinal fluid (CSF) is a readily reachable body fluid that is reflective of the underlying pathological state of the central nervous system (CNS). Hence it has been targeted for biomarker discovery for a variety of neurological disorders. CSF is also the major route [...] Read more.
Cerebrospinal fluid (CSF) is a readily reachable body fluid that is reflective of the underlying pathological state of the central nervous system (CNS). Hence it has been targeted for biomarker discovery for a variety of neurological disorders. CSF is also the major route for seeding metastases of CNS malignancies and its analysis could be informative for diagnosis and risk stratification of brain cancers. Recently, modern high-throughput, microRNAs (miRNAs) measuring technology has enabled sensitive detection of distinct miRNAs that are bio-chemicallystable in the CSF and can distinguish between different types of CNS cancers. Owing to the fact that a CSF specimen can be obtained with relative ease, analysis of CSF miRNAs could be a promising contribution to clinical practice. In this review, we examine the current scientific knowledge on tumor associated CSF miRNAs that could guide diagnosis of different brain cancer types, or could be helpful in predicting disease progression and therapy response. Finally, we highlight their potential applications clinically as biomarkers and discuss limitations. Full article
Show Figures

Graphical abstract

1755 KiB  
Review
Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism
by Jing-Wen Shih, Ling-Yu Wang, Chiu-Lien Hung, Hsing-Jien Kung and Chia-Ling Hsieh
Int. J. Mol. Sci. 2015, 16(12), 28943-28978; https://doi.org/10.3390/ijms161226138 - 04 Dec 2015
Cited by 30 | Viewed by 10087
Abstract
Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of [...] Read more.
Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed. Full article
Show Figures

Figure 1

377 KiB  
Review
MicroRNAs: Clinical Relevance in Colorectal Cancer
by Joe Thomas, Masahisa Ohtsuka, Martin Pichler and Hui Ling
Int. J. Mol. Sci. 2015, 16(12), 28063-28076; https://doi.org/10.3390/ijms161226080 - 25 Nov 2015
Cited by 107 | Viewed by 8128
Abstract
Colorectal cancer is one of the most common cancer diagnoses and causes of mortality worldwide. MicroRNAs are a class of small, non-coding regulatory RNAs that have shown strong associations with colorectal cancer. Through the repression of target messenger RNAs, microRNAs modulate many cellular [...] Read more.
Colorectal cancer is one of the most common cancer diagnoses and causes of mortality worldwide. MicroRNAs are a class of small, non-coding regulatory RNAs that have shown strong associations with colorectal cancer. Through the repression of target messenger RNAs, microRNAs modulate many cellular pathways, such as those involved in cell proliferation, apoptosis, and differentiation. The utilization of microRNAs has shown significant promise in the diagnosis and prognosis of colorectal cancer, owing to their unique expression profile associations with cancer types and malignancies. Moreover, microRNA therapeutics with mimics or antagonists show great promise in preclinical studies, which encourages further development of their clinical use for colorectal cancer patients. The unique ability of microRNAs to affect multiple downstream pathways represents a novel approach for cancer therapy. Although still early in its development, we believe that microRNAs can be used in the near future as biomarkers and therapeutic targets for colorectal cancer. Full article
Show Figures

Figure 1

1221 KiB  
Article
Benzene-Induced Aberrant miRNA Expression Profile in Hematopoietic Progenitor Cells in C57BL/6 Mice
by Haiyan Wei, Juan Zhang, Kehong Tan, Rongli Sun, Lihong Yin and Yuepu Pu
Int. J. Mol. Sci. 2015, 16(11), 27058-27071; https://doi.org/10.3390/ijms161126001 - 12 Nov 2015
Cited by 26 | Viewed by 5981
Abstract
Benzene is a common environmental pollutant that causes hematological alterations. MicroRNAs (miRNAs) may play a role in benzene-induced hematotoxicity. In this study, C57BL/6 mice showed significant hematotoxicity after exposure to 150 mg/kg benzene for 4 weeks. Benzene exposure decreased not only the number [...] Read more.
Benzene is a common environmental pollutant that causes hematological alterations. MicroRNAs (miRNAs) may play a role in benzene-induced hematotoxicity. In this study, C57BL/6 mice showed significant hematotoxicity after exposure to 150 mg/kg benzene for 4 weeks. Benzene exposure decreased not only the number of cells in peripheral blood but also hematopoietic progenitor cells in the bone marrow. Meanwhile, RNA from Lin cells sorted from the bone marrow was applied to aberrant miRNA expression profile using Illumina sequencing. We found that 5 miRNAs were overexpressed and 45 miRNAs were downregulated in the benzene exposure group. Sequencing results were confirmed through qRT-PCR. Furthermore, we also identified five miRNAs which significantly altered in Linc-Kit+ cells obtained from benzene-exposed mice, including mmu-miR-34a-5p; mmu-miR-342-3p; mmu-miR-100-5p; mmu-miR-181a-5p; and mmu-miR-196b-5p. In summary, we successfully established a classical animal model to induce significant hematotoxicity by benzene injection. Benzene exposure may cause severe hematotoxicity not only to blood cells in peripheral circulation but also to hematopoietic cells in bone marrow. Benzene exposure also alters miRNA expression in hematopoietic progenitor cells. This study suggests that benzene induces alteration in hematopoiesis and hematopoiesis-associated miRNAs. Full article
Show Figures

Graphical abstract

496 KiB  
Review
Long Non-Coding RNAs in Endometrial Carcinoma
by Maria A. Smolle, Marc D. Bullock, Hui Ling, Martin Pichler and Johannes Haybaeck
Int. J. Mol. Sci. 2015, 16(11), 26463-26472; https://doi.org/10.3390/ijms161125962 - 04 Nov 2015
Cited by 63 | Viewed by 7360
Abstract
Endometrial carcinoma (EC), the second most common form of gynaecological malignancy, can be divided into two distinct sub-types: Type I tumours arise from hyperplastic endometrium and typically effect women around the time of menopause, whereas type II tumours arise in postmenopausal women from [...] Read more.
Endometrial carcinoma (EC), the second most common form of gynaecological malignancy, can be divided into two distinct sub-types: Type I tumours arise from hyperplastic endometrium and typically effect women around the time of menopause, whereas type II tumours arise in postmenopausal women from atrophic endometrium. Long non-coding RNAs (lncRNAs) are a novel class of non-protein coding molecules that have recently been implicated in the pathogenesis of many types of cancer including gynaecological tumours. Although they play critical physiological roles in cellular metabolism, their expression and function are deregulated in EC compared with paired normal tissue, indicating that they may also participate in tumour initiation and progression. For instance, the lncRNA MALAT-1 is down-regulated in EC samples compared to normal or hyperplastic endometrium, whereas the lncRNA OVAL is down-regulated in type II disease but up-regulated in type I disease. Other notatble lncRNAs such as HOTAIR, H19 and SRA become up-regulated with increasing EC tumour grade and other features associated with poor prognosis. In the current review, we will examine the growing body of evidence linking deregulated lncRNAs with specific biological functions of tumour cells in EC, we will highlight associations between lncRNAs and the molecular pathways implicated in EC tumourigenesis and we will identify critical knowledge gaps that remain to be addressed. Full article
Show Figures

Figure 1

2752 KiB  
Review
The Role of MicroRNAs as Predictors of Response to Tamoxifen Treatment in Breast Cancer Patients
by Nina G. Egeland, Siri Lunde, Kristin Jonsdottir, Tone H. Lende, Deirdre Cronin-Fenton, Bjørnar Gilje, Emiel A. M. Janssen and Håvard Søiland
Int. J. Mol. Sci. 2015, 16(10), 24243-24275; https://doi.org/10.3390/ijms161024243 - 14 Oct 2015
Cited by 52 | Viewed by 10639
Abstract
Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. However, resistance to endocrine therapy leads to breast cancer relapse. The recent extension of adjuvant tamoxifen treatment up to 10 years actualizes the need for identifying biological markers that [...] Read more.
Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. However, resistance to endocrine therapy leads to breast cancer relapse. The recent extension of adjuvant tamoxifen treatment up to 10 years actualizes the need for identifying biological markers that may be used to monitor predictors of treatment response. MicroRNAs are promising biomarkers that may fill the gap between preclinical knowledge and clinical observations regarding endocrine resistance. MicroRNAs regulate gene expression by posttranscriptional repression or degradation of mRNA, most often leading to gene silencing. MicroRNAs have been identified directly in the primary tumor, but also in the circulation of breast cancer patients. The few available studies investigating microRNA in patients suggest that seven microRNAs (miR-10a, miR-26, miR-30c, miR-126a, miR-210, miR-342 and miR-519a) play a role in tamoxifen resistance. Ingenuity Pathway Analysis (IPA) reveals that these seven microRNAs interact more readily with estrogen receptor (ER)-independent pathways than ER-related signaling pathways. Some of these pathways are targetable (e.g., PIK3CA), suggesting that microRNAs as biomarkers of endocrine resistance may have clinical value. Validation of the role of these candidate microRNAs in large prospective studies is warranted. Full article
Show Figures

Graphical abstract

1506 KiB  
Review
Long Non-Coding RNAs as Master Regulators in Cardiovascular Diseases
by Krystal Archer, Zuzana Broskova, Ahmed S. Bayoumi, Jian-peng Teoh, Alec Davila, Yaoliang Tang, Huabo Su and Il-man Kim
Int. J. Mol. Sci. 2015, 16(10), 23651-23667; https://doi.org/10.3390/ijms161023651 - 05 Oct 2015
Cited by 139 | Viewed by 10886
Abstract
Cardiovascular disease is the leading cause of death in the United States, accounting for nearly one in every seven deaths. Over the last decade, various targeted therapeutics have been introduced, but there has been no corresponding improvement in patient survival. Since the mortality [...] Read more.
Cardiovascular disease is the leading cause of death in the United States, accounting for nearly one in every seven deaths. Over the last decade, various targeted therapeutics have been introduced, but there has been no corresponding improvement in patient survival. Since the mortality rate of cardiovascular disease has not been significantly decreased, efforts have been made to understand the link between heart disease and novel therapeutic targets such as non-coding RNAs. Among multiple non-coding RNAs, long non-coding RNA (lncRNA) has emerged as a novel therapeutic in cardiovascular medicine. LncRNAs are endogenous RNAs that contain over 200 nucleotides and regulate gene expression. Recent studies suggest critical roles of lncRNAs in modulating the initiation and progression of cardiovascular diseases. For example, aberrant lncRNA expression has been associated with the pathogenesis of ischemic heart failure. In this article, we present a synopsis of recent discoveries that link the roles and molecular interactions of lncRNAs to cardiovascular diseases. Moreover, we describe the prevalence of circulating lncRNAs and assess their potential utilities as biomarkers for diagnosis and prognosis of heart disease. Full article
Show Figures

Graphical abstract

1019 KiB  
Article
A Large-Scale Analysis of the Relationship of Synonymous SNPs Changing MicroRNA Regulation with Functionality and Disease
by Yuchen Wang, Chengxiang Qiu and Qinghua Cui
Int. J. Mol. Sci. 2015, 16(10), 23545-23555; https://doi.org/10.3390/ijms161023545 - 30 Sep 2015
Cited by 27 | Viewed by 4933
Abstract
Historically, owing to not changing amino acid composition of protein sequences, synonymous mutations are commonly assumed to be neutral during evolution and therefore have no effect on the phenotype and disease. Here, based on observations from large-scale analysis of genomic data, we predicted [...] Read more.
Historically, owing to not changing amino acid composition of protein sequences, synonymous mutations are commonly assumed to be neutral during evolution and therefore have no effect on the phenotype and disease. Here, based on observations from large-scale analysis of genomic data, we predicted the putative synonymous SNPs that could result in functional consequences and disease risk through changing the microRNA-mediated gene regulation. We found that nearly half of the synonymous SNPs could affect protein expression by changing microRNA regulation in human genome and these SNPs significantly prefer to be associated with human diseases and traits. The synonymous SNPs changing microRNA-mediated gene regulation tend to be more under recent positive selection, prefer to affect gene expression, and implicate in human disease. We conclude that the miRNA-mediated regulation changes could be a potential mechanism for the contributions of synonymous SNPs to protein functions and disease risks. Full article
Show Figures

Graphical abstract

1219 KiB  
Article
Combination of MiR-378 and MiR-210 Serum Levels Enables Sensitive Detection of Renal Cell Carcinoma
by Michal Fedorko, Michal Stanik, Robert Iliev, Martina Redova-Lojova, Tana Machackova, Marek Svoboda, Dalibor Pacik, Jan Dolezel and Ondrej Slaby
Int. J. Mol. Sci. 2015, 16(10), 23382-23389; https://doi.org/10.3390/ijms161023382 - 29 Sep 2015
Cited by 71 | Viewed by 5912
Abstract
Serum microRNAs are emerging as a clinically useful tool for early and non-invasive detection of various cancer types including renal cell carcinoma (RCC). Based on our previous results, we performed the study to analyze circulating serum miR-378 and miR-210 in patients with various [...] Read more.
Serum microRNAs are emerging as a clinically useful tool for early and non-invasive detection of various cancer types including renal cell carcinoma (RCC). Based on our previous results, we performed the study to analyze circulating serum miR-378 and miR-210 in patients with various histological subtypes of RCC. RNA was purified from blood serum samples of 195 RCC patients and 100 healthy controls. The levels of miR-378 and miR-210 in serum were determined absolutely using quantitative real-time PCR. Pre- and postoperative levels of both microRNAs were compared in 20 RCC patients. Significantly increased serum levels of both miR-378 and miR-210 enabled to clearly distinguish RCC patients and healthy controls with 80% sensitivity and 78% specificity if analyzed in combination (p < 0.0001), and their levels significantly decreased in the time period of three months after radical nephrectomy (p < 0.0001). Increased level of miR-378 positively correlates with disease-free survival (p = 0.036) and clinical stage (p = 0.0476). The analysis of serum miR-378 and miR-210 proved their potential to serve as powerful non-invasive diagnostic and prognostic biomarkers in RCC. Full article
Show Figures

Figure 1

1310 KiB  
Review
Regulatory Roles of Non-Coding RNAs in Colorectal Cancer
by Jun Wang, Yong-Xi Song, Bin Ma, Jia-Jun Wang, Jing-Xu Sun, Xiao-Wan Chen, Jun-Hua Zhao, Yu-Chong Yang and Zhen-Ning Wang
Int. J. Mol. Sci. 2015, 16(8), 19886-19919; https://doi.org/10.3390/ijms160819886 - 21 Aug 2015
Cited by 62 | Viewed by 8162
Abstract
Non-coding RNAs (ncRNAs) have recently gained attention because of their involvement in different biological processes. An increasing number of studies have demonstrated that mutations or abnormal expression of ncRNAs are closely associated with various diseases including cancer. The present review is a comprehensive [...] Read more.
Non-coding RNAs (ncRNAs) have recently gained attention because of their involvement in different biological processes. An increasing number of studies have demonstrated that mutations or abnormal expression of ncRNAs are closely associated with various diseases including cancer. The present review is a comprehensive examination of the aberrant regulation of ncRNAs in colorectal cancer (CRC) and a summary of the current findings on ncRNAs, including long ncRNAs, microRNAs, small interfering RNAs, small nucleolar RNAs, small nuclear RNAs, Piwi-interacting RNAs, and circular RNAs. These ncRNAs might become novel biomarkers and targets as well as potential therapeutic tools for the treatment of CRC in the near future and this review may provide important clues for further research on CRC and for the selection of effective therapeutic targets. Full article
Show Figures

Graphical abstract

979 KiB  
Review
LincRNA-p21: Implications in Human Diseases
by Sai-Sai Tang, Bi-Ying Zheng and Xing-Dong Xiong
Int. J. Mol. Sci. 2015, 16(8), 18732-18740; https://doi.org/10.3390/ijms160818732 - 11 Aug 2015
Cited by 58 | Viewed by 8154
Abstract
Long noncoding RNAs (lncRNAs), which lack significant protein-coding capacity, regulate various biological processes through diverse and as yet poorly understood molecular mechanisms. However, a number of studies in the past few years have documented important functions for lncRNAs in human diseases. Among these [...] Read more.
Long noncoding RNAs (lncRNAs), which lack significant protein-coding capacity, regulate various biological processes through diverse and as yet poorly understood molecular mechanisms. However, a number of studies in the past few years have documented important functions for lncRNAs in human diseases. Among these lncRNAs, lincRNA-p21 has been proposed to be a novel regulator of cell proliferation, apoptosis and DNA damage response, and involved in the initiation and progression of human diseases. In this review, we summarize the current knowledge of lincRNA-p21, mainly focus on the known biological functions and its underlying mechanisms. Moreover, we highlight the growing body of evidences for the importance of lincRNA-p21 in diverse human diseases, which indicate lincRNA-p21 as a potential diagnostic marker and/or a valuable therapeutic target for these diseases. Full article
Show Figures

Graphical abstract

1350 KiB  
Article
miR-199a and miR-497 Are Associated with Better Overall Survival due to Increased Chemosensitivity in Diffuse Large B-Cell Lymphoma Patients
by Katharina Troppan, Kerstin Wenzl, Martin Pichler, Beata Pursche, Daniela Schwarzenbacher, Julia Feichtinger, Gerhard G. Thallinger, Christine Beham-Schmid, Peter Neumeister and Alexander Deutsch
Int. J. Mol. Sci. 2015, 16(8), 18077-18095; https://doi.org/10.3390/ijms160818077 - 05 Aug 2015
Cited by 55 | Viewed by 6079
Abstract
Micro-RNAs (miRNAs) are short non-coding single-stranded RNA molecules regulating gene expression at the post-transcriptional level. miRNAs are involved in cell development, differentiation, apoptosis, and proliferation. miRNAs can either function as tumor suppressor genes or oncogenes in various important pathways. The expression of specific [...] Read more.
Micro-RNAs (miRNAs) are short non-coding single-stranded RNA molecules regulating gene expression at the post-transcriptional level. miRNAs are involved in cell development, differentiation, apoptosis, and proliferation. miRNAs can either function as tumor suppressor genes or oncogenes in various important pathways. The expression of specific miRNAs has been identified to correlate with tumor prognosis. For miRNA expression analysis real-time PCR on 81 samples was performed, including 63 diffuse large B-cell lymphoma (DLBCL, 15 of germinal center B-cell like subtype, 17 non germinal center B-cell, 23 transformed, and eight unclassified) and 18 controls, including nine peripheral B-cells, 5 germinal-center B-cells, four lymphadenitis samples, and 4 lymphoma cell lines (RI-1, SUDHL4, Karpas, U2932). Expression levels of a panel of 11 miRNAs that have been previously involved in other types of cancer (miR-15b_2, miR-16_1*, miR-16_2, miR-16_2*, miR-27a, miR-27a*, miR-98-1, miR-103a, miR-185, miR-199a, and miR-497) were measured and correlated with clinical data. Furthermore, cell lines, lacking miR-199a and miR-497 expression, were electroporated with the two respective miRNAs and treated with standard immunochemotherapy routinely used in patients with DLBCL, followed by functional analyses including cell count and apoptosis assays. Seven miRNAs (miR-16_1*, miR-16_2*, miR-27a, miR-103, miR-185, miR-199, and miR-497) were statistically significantly up-regulated in DLBCL compared to normal germinal cells. However, high expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL. Full article
Show Figures

Graphical abstract

870 KiB  
Review
What Do We Know about the Role of miRNAs in Pediatric Sarcoma?
by Lorna C. Kelly, Antonio Lázaro and Maureen J. O'Sullivan
Int. J. Mol. Sci. 2015, 16(7), 16593-16621; https://doi.org/10.3390/ijms160716593 - 22 Jul 2015
Cited by 3 | Viewed by 5553
Abstract
Non-coding RNAs have received a lot of attention in recent years, with especial focus on microRNAs (miRNAs), so much so that in the just over two decades since the first miRNA, Lin4, was described, almost 40,000 publications about miRNAs have been generated. [...] Read more.
Non-coding RNAs have received a lot of attention in recent years, with especial focus on microRNAs (miRNAs), so much so that in the just over two decades since the first miRNA, Lin4, was described, almost 40,000 publications about miRNAs have been generated. Less than 500 of these focus on sarcoma, and only a fraction of those on sarcomas of childhood specifically, with some of these representing observational studies and others containing functionally validated data. This is a group of cancers for which prognosis is often poor and therapeutic options limited, and it is especially in these areas that strides in understanding the role of non-coding RNAs and miRNAs in particular are to be welcomed. This review deals with the main forms of pediatric sarcoma, exploring what is known about the diagnostic and prognostic profiles of miRNAs in these tumours and where novel therapeutic options might present themselves for further exploration. Full article
Show Figures

Graphical abstract

898 KiB  
Review
Families of microRNAs Expressed in Clusters Regulate Cell Signaling in Cervical Cancer
by Luis Steven Servín-González, Angelica Judith Granados-López and Jesús Adrián López
Int. J. Mol. Sci. 2015, 16(6), 12773-12790; https://doi.org/10.3390/ijms160612773 - 05 Jun 2015
Cited by 43 | Viewed by 8810
Abstract
Tumor cells have developed advantages to acquire hallmarks of cancer like apoptosis resistance, increased proliferation, migration, and invasion through cell signaling pathway misregulation. The sequential activation of genes in a pathway is regulated by miRNAs. Loss or gain of miRNA expression could activate [...] Read more.
Tumor cells have developed advantages to acquire hallmarks of cancer like apoptosis resistance, increased proliferation, migration, and invasion through cell signaling pathway misregulation. The sequential activation of genes in a pathway is regulated by miRNAs. Loss or gain of miRNA expression could activate or repress a particular cell axis. It is well known that aberrant miRNA expression is well recognized as an important step in the development of cancer. Individual miRNA expression is reported without considering that miRNAs are grouped in clusters and may have similar functions, such as the case of clusters with anti-oncomiRs (23b~27b~24-1, miR-29a~29b-1, miR-29b-2~29c, miR-99a~125b-2, miR-99b~125a, miR-100~125b-1, miR-199a-2~214, and miR-302s) or oncomiRs activity (miR-1-1~133a-2, miR-1-2~133a-1, miR-133b~206, miR-17~92, miR-106a~363, miR183~96~182, miR-181a-1~181b-1, and miR-181a-2~181b-2), which regulated mitogen-activated protein kinases (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), NOTCH, proteasome-culling rings, and apoptosis cell signaling. In this work we point out the pathways regulated by families of miRNAs grouped in 20 clusters involved in cervical cancer. Reviewing how miRNA families expressed in cluster-regulated cell path signaling will increase the knowledge of cervical cancer progression, providing important information for therapeutic, diagnostic, and prognostic methodology design. Full article
Show Figures

Figure 1

4265 KiB  
Article
Regulative Effect of Mir-205 on Osteogenic Differentiation of Bone Mesenchymal Stem Cells (BMSCs): Possible Role of SATB2/Runx2 and ERK/MAPK Pathway
by Nan Hu, Chunzhen Feng, Yi Jiang, Qing Miao and Hongchen Liu
Int. J. Mol. Sci. 2015, 16(5), 10491-10506; https://doi.org/10.3390/ijms160510491 - 07 May 2015
Cited by 98 | Viewed by 7794
Abstract
Bone mesenchymal stem cells (BMSCs) have multiple potentials to differentiate into osteoblasts and adipocytes, and methods to enhance their osteogenic differentiation are gaining increasing attention. MicroRNAs are critical regulation factors during the process of the osteogenic induction in BMSCs, and mir-205 has been [...] Read more.
Bone mesenchymal stem cells (BMSCs) have multiple potentials to differentiate into osteoblasts and adipocytes, and methods to enhance their osteogenic differentiation are gaining increasing attention. MicroRNAs are critical regulation factors during the process of the osteogenic induction in BMSCs, and mir-205 has been substantiated to be involved in the osteogenic process, but the underlying mechanisms remain unclear. The purpose of this article is to investigate the role of mir-205 in the osteogenic differentiation of BMSCs. We found that mir-205 expression was down-regulated in a time-dependent manner during BMSC osteo-induction. Inhibition of mir-205 enhanced osteogenic abilities by up-regulating bone sialoprotein (BSP) and osteopontin (OPN) protein levels and increasing alkaline phosphatase (ALP) activity and osteocalcin secretion. Furthermore, we found that mir-205 could regulate protein expression of special AT-rich sequence-binding protein 2 (SATB2) and runt-related transcription factor 2 (Runx2), and over-expression of SATB2 activated Runx2 and reversed the negative effects of mir-205 on osteoblastic differentiation. Furthermore, we examined the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways during osteogenic induction and our data indicates that mir-205 might exert negative functions on the osteogenic differentiation in BMSCs at least partly via altering phosphorylation of ERK and p38 MAPK. These results shed new light on the molecular mechanisms of microRNAs in governing differentiation of BMSCs. Full article
Show Figures

Figure 1

2876 KiB  
Article
The miRNA Transcriptome Directly Reflects the Physiological and Biochemical Differences between Red, White, and Intermediate Muscle Fiber Types
by Jideng Ma, Hongmei Wang, Rui Liu, Long Jin, Qianzi Tang, Xun Wang, Anan Jiang, Yaodong Hu, Zongwen Li, Li Zhu, Ruiqiang Li, Mingzhou Li and Xuewei Li
Int. J. Mol. Sci. 2015, 16(5), 9635-9653; https://doi.org/10.3390/ijms16059635 - 29 Apr 2015
Cited by 20 | Viewed by 9352
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that can regulate their target genes at the post-transcriptional level. Skeletal muscle comprises different fiber types that can be broadly classified as red, intermediate, and white. Recently, a set of miRNAs was found expressed in a fiber [...] Read more.
MicroRNAs (miRNAs) are small non-coding RNAs that can regulate their target genes at the post-transcriptional level. Skeletal muscle comprises different fiber types that can be broadly classified as red, intermediate, and white. Recently, a set of miRNAs was found expressed in a fiber type-specific manner in red and white fiber types. However, an in-depth analysis of the miRNA transcriptome differences between all three fiber types has not been undertaken. Herein, we collected 15 porcine skeletal muscles from different anatomical locations, which were then clearly divided into red, white, and intermediate fiber type based on the ratios of myosin heavy chain isoforms. We further illustrated that three muscles, which typically represented each muscle fiber type (i.e., red: peroneal longus (PL), intermediate: psoas major muscle (PMM), white: longissimus dorsi muscle (LDM)), have distinct metabolic patterns of mitochondrial and glycolytic enzyme levels. Furthermore, we constructed small RNA libraries for PL, PMM, and LDM using a deep sequencing approach. Results showed that the differentially expressed miRNAs were mainly enriched in PL and played a vital role in myogenesis and energy metabolism. Overall, this comprehensive analysis will contribute to a better understanding of the miRNA regulatory mechanism that achieves the phenotypic diversity of skeletal muscles. Full article
Show Figures

Figure 1

8861 KiB  
Article
Micro RNA-124a Regulates Lipolysis via Adipose Triglyceride Lipase and Comparative Gene Identification 58
by Suman K. Das, Elke Stadelmeyer, Silvia Schauer, Anna Schwarz, Heimo Strohmaier, Thiery Claudel, Rudolf Zechner, Gerald Hoefler and Paul W. Vesely
Int. J. Mol. Sci. 2015, 16(4), 8555-8568; https://doi.org/10.3390/ijms16048555 - 16 Apr 2015
Cited by 24 | Viewed by 7618
Abstract
Lipolysis is the biochemical pathway responsible for the catabolism of cellular triacylglycerol (TG). Lipolytic TG breakdown is a central metabolic process leading to the generation of free fatty acids (FA) and glycerol, thereby regulating lipid, as well as energy homeostasis. The precise tuning [...] Read more.
Lipolysis is the biochemical pathway responsible for the catabolism of cellular triacylglycerol (TG). Lipolytic TG breakdown is a central metabolic process leading to the generation of free fatty acids (FA) and glycerol, thereby regulating lipid, as well as energy homeostasis. The precise tuning of lipolysis is imperative to prevent lipotoxicity, obesity, diabetes and other related metabolic disorders. Here, we present our finding that miR-124a attenuates RNA and protein expression of the major TG hydrolase, adipose triglyceride lipase (ATGL/PNPLA2) and its co-activator comparative gene identification 58 (CGI-58/ABHD5). Ectopic expression of miR-124a in adipocytes leads to reduced lipolysis and increased cellular TG accumulation. This phenotype, however, can be rescued by overexpression of truncated Atgl lacking its 3'UTR, which harbors the identified miR-124a target site. In addition, we observe a strong negative correlation between miR-124a and Atgl expression in various murine tissues. Moreover, miR-124a regulates the expression of Atgl and Cgi-58 in murine white adipose tissue during fasting as well as the expression of Atgl in murine liver, during fasting and re-feeding. Together, these results point to an instrumental role of miR-124a in the regulation of TG catabolism. Therefore, we suggest that miR-124a may be involved in the regulation of several cellular and organismal metabolic parameters, including lipid storage and plasma FA concentration. Full article
Show Figures

Figure 1

1027 KiB  
Article
Resistance Training Regulates Cardiac Function through Modulation of miRNA-214
by Stéphano Freitas Soares Melo, Valério Garrone Barauna, Miguel Araújo Carneiro Júnior, Luiz Henrique Marchesi Bozi, Lucas Rios Drummond, Antônio José Natali and Edilamar Menezes De Oliveira
Int. J. Mol. Sci. 2015, 16(4), 6855-6867; https://doi.org/10.3390/ijms16046855 - 26 Mar 2015
Cited by 41 | Viewed by 6828
Abstract
Aims: To determine the effects of resistance training (RT) on the expression of microRNA (miRNA)-214 and its target in sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), and on the morphological and mechanical properties of isolated left ventricular myocytes. Main methods: Male Wistar rats were [...] Read more.
Aims: To determine the effects of resistance training (RT) on the expression of microRNA (miRNA)-214 and its target in sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), and on the morphological and mechanical properties of isolated left ventricular myocytes. Main methods: Male Wistar rats were divided into two groups (n = 7/group): Control (CO) or trained (TR). The exercise-training protocol consisted of: 4 × 12 bouts, 5×/week during 8 weeks, with 80% of one repetition maximum. Key findings: RT increased the left ventricular myocyte width by 15% and volume by 12%, compared with control animals (p < 0.05). The time to half relaxation and time to peak were 8.4% and 4.4% lower, respectively, in cells from TR group as compared to CO group (p < 0.05). RT decreased miRNA-214 level by 18.5% while its target SERCA2a expression were 18.5% higher (p < 0.05). Significance: Our findings showed that RT increases single left ventricular myocyte dimensions and also leads to faster cell contraction and relaxation. These mechanical adaptations may be related to the augmented expression of SERCA2a which, in turn, may be associated with the epigenetic modification of decreased miRNA-214 expression. Full article
Show Figures

Figure 1

1688 KiB  
Review
Exploring the Secrets of Long Noncoding RNAs
by Mingyang Quan, Jinhui Chen and Deqiang Zhang
Int. J. Mol. Sci. 2015, 16(3), 5467-5496; https://doi.org/10.3390/ijms16035467 - 10 Mar 2015
Cited by 108 | Viewed by 9384
Abstract
High-throughput sequencing has revealed that the majority of RNAs have no capacity to encode protein. Among these non-coding transcripts, recent work has focused on the roles of long noncoding RNAs (lncRNAs) of >200 nucleotides. Although many of their attributes, such as patterns of [...] Read more.
High-throughput sequencing has revealed that the majority of RNAs have no capacity to encode protein. Among these non-coding transcripts, recent work has focused on the roles of long noncoding RNAs (lncRNAs) of >200 nucleotides. Although many of their attributes, such as patterns of expression, remain largely unknown, lncRNAs have key functions in transcriptional, post-transcriptional, and epigenetic gene regulation; Also, new work indicates their functions in scaffolding ribonuclear protein complexes. In plants, genome-wide identification of lncRNAs has been conducted in several species, including Zea mays, and recent research showed that lncRNAs regulate flowering time in the photoperiod pathway, and function in nodulation. In this review, we discuss the basic mechanisms by which lncRNAs regulate key cellular processes, using the large body of knowledge on animal and yeast lncRNAs to illustrate the significance of emerging work on lncRNAs in plants. Full article
Show Figures

Figure 1

2020 KiB  
Review
Monitoring the Spatiotemporal Activities of miRNAs in Small Animal Models Using Molecular Imaging Modalities
by Patrick Baril, Safia Ezzine and Chantal Pichon
Int. J. Mol. Sci. 2015, 16(3), 4947-4972; https://doi.org/10.3390/ijms16034947 - 04 Mar 2015
Cited by 14 | Viewed by 7365
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression by binding mRNA targets via sequence complementary inducing translational repression and/or mRNA degradation. A current challenge in the field of miRNA biology is to understand the functionality of miRNAs under [...] Read more.
MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression by binding mRNA targets via sequence complementary inducing translational repression and/or mRNA degradation. A current challenge in the field of miRNA biology is to understand the functionality of miRNAs under physiopathological conditions. Recent evidence indicates that miRNA expression is more complex than simple regulation at the transcriptional level. MiRNAs undergo complex post-transcriptional regulations such miRNA processing, editing, accumulation and re-cycling within P-bodies. They are dynamically regulated and have a well-orchestrated spatiotemporal localization pattern. Real-time and spatio-temporal analyses of miRNA expression are difficult to evaluate and often underestimated. Therefore, important information connecting miRNA expression and function can be lost. Conventional miRNA profiling methods such as Northern blot, real-time PCR, microarray, in situ hybridization and deep sequencing continue to contribute to our knowledge of miRNA biology. However, these methods can seldom shed light on the spatiotemporal organization and function of miRNAs in real-time. Non-invasive molecular imaging methods have the potential to address these issues and are thus attracting increasing attention. This paper reviews the state-of-the-art of methods used to detect miRNAs and discusses their contribution in the emerging field of miRNA biology and therapy. Full article
Show Figures

Figure 1

2251 KiB  
Review
Neighboring Gene Regulation by Antisense Long Non-Coding RNAs
by Victoria E. Villegas and Peter G. Zaphiropoulos
Int. J. Mol. Sci. 2015, 16(2), 3251-3266; https://doi.org/10.3390/ijms16023251 - 03 Feb 2015
Cited by 235 | Viewed by 14860
Abstract
Antisense transcription, considered until recently as transcriptional noise, is a very common phenomenon in human and eukaryotic transcriptomes, operating in two ways based on whether the antisense RNA acts in cis or in trans. This process can generate long non-coding RNAs (lncRNAs), [...] Read more.
Antisense transcription, considered until recently as transcriptional noise, is a very common phenomenon in human and eukaryotic transcriptomes, operating in two ways based on whether the antisense RNA acts in cis or in trans. This process can generate long non-coding RNAs (lncRNAs), one of the most diverse classes of cellular transcripts, which have demonstrated multifunctional roles in fundamental biological processes, including embryonic pluripotency, differentiation and development. Antisense lncRNAs have been shown to control nearly every level of gene regulation—pretranscriptional, transcriptional and posttranscriptional—through DNA–RNA, RNA–RNA or protein–RNA interactions. This review is centered on functional studies of antisense lncRNA-mediated regulation of neighboring gene expression. Specifically, it addresses how these transcripts interact with other biological molecules, nucleic acids and proteins, to regulate gene expression through chromatin remodeling at the pretranscriptional level and modulation of transcriptional and post-transcriptional processes by altering the sense mRNA structure or the cellular compartmental distribution, either in the nucleus or the cytoplasm. Full article
Show Figures

Graphical abstract

2121 KiB  
Article
Prediction of Mature MicroRNA and Piwi-Interacting RNA without a Genome Reference or Precursors
by Mark S. Menor, Kyungim Baek and Guylaine Poisson
Int. J. Mol. Sci. 2015, 16(1), 1466-1481; https://doi.org/10.3390/ijms16011466 - 08 Jan 2015
Cited by 10 | Viewed by 5949
Abstract
The discovery of novel microRNA (miRNA) and piwi-interacting RNA (piRNA) is an important task for the understanding of many biological processes. Most of the available miRNA and piRNA identification methods are dependent on the availability of the organism’s genome sequence and the quality [...] Read more.
The discovery of novel microRNA (miRNA) and piwi-interacting RNA (piRNA) is an important task for the understanding of many biological processes. Most of the available miRNA and piRNA identification methods are dependent on the availability of the organism’s genome sequence and the quality of its annotation. Therefore, an efficient prediction method based solely on the short RNA reads and requiring no genomic information is highly desirable. In this study, we propose an approach that relies primarily on the nucleotide composition of the read and does not require reference genomes of related species for prediction. Using an empirical Bayesian kernel method and the error correcting output codes framework, compact models suitable for large-scale analyses are built on databases of known mature miRNAs and piRNAs. We found that the usage of an L1-based Gaussian kernel can double the true positive rate compared to the standard L2-based Gaussian kernel. Our approach can increase the true positive rate by at most 60% compared to the existing piRNA predictor based on the analysis of a hold-out test set. Using experimental data, we also show that our approach can detect about an order of magnitude or more known miRNAs than the mature miRNA predictor, miRPlex. Full article
Show Figures

Figure 1

4241 KiB  
Article
MicroRNA Expression Profiling of Lactating Mammary Gland in Divergent Phenotype Swine Breeds
by Jing Peng, Jun-Sheng Zhao, Yi-Fei Shen, Hai-Guang Mao and Ning-Ying Xu
Int. J. Mol. Sci. 2015, 16(1), 1448-1465; https://doi.org/10.3390/ijms16011448 - 08 Jan 2015
Cited by 27 | Viewed by 6370
Abstract
MicroRNA (miRNA) plays a key role in development and specific biological processes, such as cell proliferation, differentiation, and apoptosis. Extensive studies of mammary miRNAs have been performed in different species and tissues. However, little is known about porcine mammary gland miRNAs. In this [...] Read more.
MicroRNA (miRNA) plays a key role in development and specific biological processes, such as cell proliferation, differentiation, and apoptosis. Extensive studies of mammary miRNAs have been performed in different species and tissues. However, little is known about porcine mammary gland miRNAs. In this study, we report the identification and characterization of miRNAs in the lactating mammary gland in two distinct pig breeds, Jinhua and Yorkshire. Many miRNAs were detected as significantly differentially expressed between the two libraries. Among the differentially expressed miRNAs, many are known to be related to mammary gland development and lactation by interacting with putative target genes in previous studies. These findings suggest that miRNA expression patterns may contribute significantly to target mRNA regulation and influence mammary gland development and peak lactation performance. The data we obtained provide useful information about the roles of miRNAs in the biological processes of lactation and the mechanisms of target gene expression and regulation. Full article
Show Figures

Graphical abstract

1385 KiB  
Review
Long Non-Coding RNAs in Cancer and Development: Where Do We Go from Here?
by Monika Haemmerle and Tony Gutschner
Int. J. Mol. Sci. 2015, 16(1), 1395-1405; https://doi.org/10.3390/ijms16011395 - 08 Jan 2015
Cited by 75 | Viewed by 8514
Abstract
Recent genome-wide expression profiling studies have uncovered a huge amount of novel, long non-protein-coding RNA transcripts (lncRNA). In general, these transcripts possess a low, but tissue-specific expression, and their nucleotide sequences are often poorly conserved. However, several studies showed that lncRNAs can have [...] Read more.
Recent genome-wide expression profiling studies have uncovered a huge amount of novel, long non-protein-coding RNA transcripts (lncRNA). In general, these transcripts possess a low, but tissue-specific expression, and their nucleotide sequences are often poorly conserved. However, several studies showed that lncRNAs can have important roles for normal tissue development and regulate cellular pluripotency as well as differentiation. Moreover, lncRNAs are implicated in the control of multiple molecular pathways leading to gene expression changes and thus, ultimately modulate cell proliferation, migration and apoptosis. Consequently, deregulation of lncRNA expression contributes to carcinogenesis and is associated with human diseases, e.g., neurodegenerative disorders like Alzheimer’s Disease. Here, we will focus on some major challenges of lncRNA research, especially loss-of-function studies. We will delineate strategies for lncRNA gene targeting in vivo, and we will briefly discuss important consideration and pitfalls when investigating lncRNA functions in knockout animal models. Finally, we will highlight future opportunities for lncRNAs research by applying the concept of cross-species comparison, which might contribute to novel disease biomarker discovery and might identify lncRNAs as potential therapeutic targets. Full article
Show Figures

Figure 1

863 KiB  
Article
Telomerase Reverse Transcriptase Regulates microRNAs
by Timo Lassmann, Yoshiko Maida, Yasuhiro Tomaru, Mami Yasukawa, Yoshinari Ando, Miki Kojima, Vivi Kasim, Christophe Simon, Carsten O. Daub, Piero Carninci, Yoshihide Hayashizaki and Kenkichi Masutomi
Int. J. Mol. Sci. 2015, 16(1), 1192-1208; https://doi.org/10.3390/ijms16011192 - 06 Jan 2015
Cited by 20 | Viewed by 7336
Abstract
MicroRNAs are small non-coding RNAs that inhibit the translation of target mRNAs. In humans, most microRNAs are transcribed by RNA polymerase II as long primary transcripts and processed by sequential cleavage of the two RNase III enzymes, DROSHA and DICER, into precursor and [...] Read more.
MicroRNAs are small non-coding RNAs that inhibit the translation of target mRNAs. In humans, most microRNAs are transcribed by RNA polymerase II as long primary transcripts and processed by sequential cleavage of the two RNase III enzymes, DROSHA and DICER, into precursor and mature microRNAs, respectively. Although the fundamental functions of microRNAs in RNA silencing have been gradually uncovered, less is known about the regulatory mechanisms of microRNA expression. Here, we report that telomerase reverse transcriptase (TERT) extensively affects the expression levels of mature microRNAs. Deep sequencing-based screens of short RNA populations revealed that the suppression of TERT resulted in the downregulation of microRNAs expressed in THP-1 cells and HeLa cells. Primary and precursor microRNA levels were also reduced under the suppression of TERT. Similar results were obtained with the suppression of either BRG1 (also called SMARCA4) or nucleostemin, which are proteins interacting with TERT and functioning beyond telomeres. These results suggest that TERT regulates microRNAs at the very early phases in their biogenesis, presumably through non-telomerase mechanism(s). Full article
Show Figures

Figure 1

2014

Jump to: 2023, 2022, 2021, 2020, 2019, 2018, 2017, 2016, 2015

1422 KiB  
Review
MicroRNA Signatures as Biomarkers and Therapeutic Target for CNS Embryonal Tumors: The Pros and the Cons
by Tarek Shalaby, Giulio Fiaschetti, Martin Baumgartner and Michael A. Grotzer
Int. J. Mol. Sci. 2014, 15(11), 21554-21586; https://doi.org/10.3390/ijms151121554 - 24 Nov 2014
Cited by 29 | Viewed by 7982
Abstract
Embryonal tumors of the central nervous system represent a heterogeneous group of childhood cancers with an unknown pathogenesis; diagnosis, on the basis of histological appearance alone, is controversial and patients’ response to therapy is difficult to predict. They encompass medulloblastoma, atypical teratoid/rhabdoid tumors [...] Read more.
Embryonal tumors of the central nervous system represent a heterogeneous group of childhood cancers with an unknown pathogenesis; diagnosis, on the basis of histological appearance alone, is controversial and patients’ response to therapy is difficult to predict. They encompass medulloblastoma, atypical teratoid/rhabdoid tumors and a group of primitive neuroectodermal tumors. All are aggressive tumors with the tendency to disseminate throughout the central nervous system. The large amount of genomic and molecular data generated over the last 5–10 years encourages optimism that new molecular targets will soon improve outcomes. Recent neurobiological studies have uncovered the key role of microRNAs (miRNAs) in embryonal tumors biology and their potential use as biomarkers is increasingly being recognized and investigated. However the successful use of microRNAs as reliable biomarkers for the detection and management of pediatric brain tumors represents a substantial challenge. This review debates the importance of miRNAs in the biology of central nervous systemembryonal tumors focusing on medulloblastoma and atypical teratoid/rhabdoid tumors and highlights the advantages as well as the limitations of their prospective application as biomarkers and candidates for molecular therapeutic targets. Full article
Show Figures

Figure 1

1408 KiB  
Review
Long Non-Coding RNAs: Critical Players in Hepatocellular Carcinoma
by Jin Sun, Beibei Bie, Shu Zhang, Jun Yang and Zongfang Li
Int. J. Mol. Sci. 2014, 15(11), 20434-20448; https://doi.org/10.3390/ijms151120434 - 07 Nov 2014
Cited by 43 | Viewed by 6527
Abstract
Hepatocellular carcinoma (HCC) is a complex disease with multiple underlying pathogenic mechanisms caused by a variety of etiologic factors. Emerging evidence showed that long non-coding RNAs (lncRNAs), with size larger than 200 nucleotides (nt), play important roles in various types of cancer development [...] Read more.
Hepatocellular carcinoma (HCC) is a complex disease with multiple underlying pathogenic mechanisms caused by a variety of etiologic factors. Emerging evidence showed that long non-coding RNAs (lncRNAs), with size larger than 200 nucleotides (nt), play important roles in various types of cancer development and progression. In recent years, some dysregulated lncRNAs in HCC have been revealed and roles for several of them in HCC have been characterized. All these findings point to the potential of lncRNAs as prospective novel therapeutic targets in HCC. In this review, we summarize known dysregulated lncRNAs in HCC, and review potential biological roles and underlying molecular mechanisms of lncRNAs in HCC. Additionally, we discussed prospects of lncRNAs as potential biomarker and therapeutic target for HCC. In conclusion, this paper will help us gain better understanding of molecular mechanisms by which lncRNAs perform their function in HCC and also provide general strategies and directions for future research. Full article
Show Figures

Figure 1

428 KiB  
Review
Hunting the Needle in the Haystack: A Guide to Obtain Biologically Meaningful MicroRNA Targets
by Michael Karbiener, Christina Glantschnig and Marcel Scheideler
Int. J. Mol. Sci. 2014, 15(11), 20266-20289; https://doi.org/10.3390/ijms151120266 - 06 Nov 2014
Cited by 19 | Viewed by 6519
Abstract
MicroRNAs (miRNAs) are endogenous small non-coding RNAs of ~23 nucleotides in length that form up a novel class of regulatory determinants, with a large set of target mRNAs postulated for every single miRNA. Thousands of miRNAs have been discovered so far, with hundreds [...] Read more.
MicroRNAs (miRNAs) are endogenous small non-coding RNAs of ~23 nucleotides in length that form up a novel class of regulatory determinants, with a large set of target mRNAs postulated for every single miRNA. Thousands of miRNAs have been discovered so far, with hundreds of them shown to govern biological processes with impact on disease. However, very little is known about how they specifically interfere with biological pathways and disease mechanisms. To investigate this interaction, the hunt for direct miRNA targets that mediate the miRNA effects—the “needle in the haystack”—is an essential step. In this review we provide a comprehensive workflow of successfully applied methods starting from the identification of putative miRNA-target pairs, followed by validation of direct miRNA–mRNA interactions, and finally presenting methods that dissect the impact of particular miRNA-target pairs on a biological process or disease. This guide allows the way to be paved for obtaining biologically meaningful miRNA targets. Full article
Show Figures

Graphical abstract

816 KiB  
Article
MicroRNAs Associated with the Efficacy of Photodynamic Therapy in Biliary Tract Cancer Cell Lines
by Andrej Wagner, Christian Mayr, Doris Bach, Romana Illig, Kristjan Plaetzer, Frieder Berr, Martin Pichler, Daniel Neureiter and Tobias Kiesslich
Int. J. Mol. Sci. 2014, 15(11), 20134-20157; https://doi.org/10.3390/ijms151120134 - 05 Nov 2014
Cited by 19 | Viewed by 7142
Abstract
Photodynamic therapy (PDT) is a palliative treatment option for unresectable hilar biliary tract cancer (BTC) showing a considerable benefit for survival and quality of life with few side effects. Currently, factors determining the cellular response of BTC cells towards PDT are unknown. Due [...] Read more.
Photodynamic therapy (PDT) is a palliative treatment option for unresectable hilar biliary tract cancer (BTC) showing a considerable benefit for survival and quality of life with few side effects. Currently, factors determining the cellular response of BTC cells towards PDT are unknown. Due to their multifaceted nature, microRNAs (miRs) are a promising analyte to investigate the cellular mechanisms following PDT. For two photosensitizers, Photofrin® and Foscan®, the phototoxicity was investigated in eight BTC cell lines. Each cell line (untreated) was profiled for expression of n = 754 miRs using TaqMan® Array Human MicroRNA Cards. Statistical analysis and bioinformatic tools were used to identify miRs associated with PDT efficiency and their putative targets, respectively. Twenty miRs correlated significantly with either high or low PDT efficiency. PDT was particularly effective in cells with high levels of clustered miRs 25-93*-106b and (in case of miR-106b) a phenotype characterized by high expression of the mesenchymal marker vimentin and high proliferation (cyclinD1 and Ki67 expression). Insensitivity towards PDT was associated with high miR-200 family expression and (for miR-cluster 200a/b-429) expression of differentiation markers Ck19 and Ck8/18. Predicted and validated downstream targets indicate plausible involvement of miRs 20a*, 25, 93*, 130a, 141, 200a, 200c and 203 in response mechanisms to PDT, suggesting that targeting these miRs could improve susceptibility to PDT in insensitive cell lines. Taken together, the miRNome pattern may provide a novel tool for predicting the efficiency of PDT and—following appropriate functional verification—may subsequently allow for optimization of the PDT protocol. Full article
Show Figures

Figure 1

1162 KiB  
Review
Small Engine, Big Power: MicroRNAs as Regulators of Cardiac Diseases and Regeneration
by Darukeshwara Joladarashi, Rajarajan A. Thandavarayan, Sahana Suresh Babu and Prasanna Krishnamurthy
Int. J. Mol. Sci. 2014, 15(9), 15891-15911; https://doi.org/10.3390/ijms150915891 - 09 Sep 2014
Cited by 38 | Viewed by 11590
Abstract
Cardiac diseases are the predominant cause of human mortality in the United States and around the world. MicroRNAs (miRNAs) are small non-coding RNAs that have been shown to modulate a wide range of biological functions under various pathophysiological conditions. miRNAs alter target expression [...] Read more.
Cardiac diseases are the predominant cause of human mortality in the United States and around the world. MicroRNAs (miRNAs) are small non-coding RNAs that have been shown to modulate a wide range of biological functions under various pathophysiological conditions. miRNAs alter target expression by post-transcriptional regulation of gene expression. Numerous studies have implicated specific miRNAs in cardiovascular development, pathology, regeneration and repair. These observations suggest that miRNAs are potential therapeutic targets to prevent or treat cardiovascular diseases. This review focuses on the emerging role of miRNAs in cardiac development, pathogenesis of cardiovascular diseases, cardiac regeneration and stem cell-mediated cardiac repair. We also discuss the novel diagnostic and therapeutic potential of these miRNAs and their targets in patients with cardiac diseases. Full article
Show Figures

Graphical abstract

2177 KiB  
Review
Multistep Model of Cervical Cancer: Participation of miRNAs and Coding Genes
by Angelica Judith Granados López and Jesús Adrián López
Int. J. Mol. Sci. 2014, 15(9), 15700-15733; https://doi.org/10.3390/ijms150915700 - 04 Sep 2014
Cited by 53 | Viewed by 7748
Abstract
Aberrant miRNA expression is well recognized as an important step in the development of cancer. Close to 70 microRNAs (miRNAs) have been implicated in cervical cancer up to now, nevertheless it is unknown if aberrant miRNA expression causes the onset of cervical cancer. [...] Read more.
Aberrant miRNA expression is well recognized as an important step in the development of cancer. Close to 70 microRNAs (miRNAs) have been implicated in cervical cancer up to now, nevertheless it is unknown if aberrant miRNA expression causes the onset of cervical cancer. One of the best ways to address this issue is through a multistep model of carcinogenesis. In the progression of cervical cancer there are three well-established steps to reach cancer that we used in the model proposed here. The first step of the model comprises the gene changes that occur in normal cells to be transformed into immortal cells (CIN 1), the second comprises immortal cell changes to tumorigenic cells (CIN 2), the third step includes cell changes to increase tumorigenic capacity (CIN 3), and the final step covers tumorigenic changes to carcinogenic cells. Altered miRNAs and their target genes are located in each one of the four steps of the multistep model of carcinogenesis. miRNA expression has shown discrepancies in different works; therefore, in this model we include miRNAs recording similar results in at least two studies. The present model is a useful insight into studying potential prognostic, diagnostic, and therapeutic miRNAs. Full article
Show Figures

Figure 1

657 KiB  
Review
MicroRNAs, Genomic Instability and Cancer
by Kimberly Vincent, Martin Pichler, Gyeong-Won Lee and Hui Ling
Int. J. Mol. Sci. 2014, 15(8), 14475-14491; https://doi.org/10.3390/ijms150814475 - 20 Aug 2014
Cited by 46 | Viewed by 9995
Abstract
MicroRNAs (miRNAs) are small non-coding RNA transcripts approximately 20 nucleotides in length that regulate expression of protein-coding genes via complementary binding mechanisms. The last decade has seen an exponential increase of publications on miRNAs, ranging from every aspect of basic cancer biology to [...] Read more.
MicroRNAs (miRNAs) are small non-coding RNA transcripts approximately 20 nucleotides in length that regulate expression of protein-coding genes via complementary binding mechanisms. The last decade has seen an exponential increase of publications on miRNAs, ranging from every aspect of basic cancer biology to diagnostic and therapeutic explorations. In this review, we summarize findings of miRNA involvement in genomic instability, an interesting but largely neglected topic to date. We discuss the potential mechanisms by which miRNAs induce genomic instability, considered to be one of the most important driving forces of cancer initiation and progression, though its precise mechanisms remain elusive. We classify genomic instability mechanisms into defects in cell cycle regulation, DNA damage response, and mitotic separation, and review the findings demonstrating the participation of specific miRNAs in such mechanisms. Full article
Show Figures

Graphical abstract

1096 KiB  
Review
Current Status of Long Non-Coding RNAs in Human Cancer with Specific Focus on Colorectal Cancer
by Maria Smolle, Stefan Uranitsch, Armin Gerger, Martin Pichler and Johannes Haybaeck
Int. J. Mol. Sci. 2014, 15(8), 13993-14013; https://doi.org/10.3390/ijms150813993 - 12 Aug 2014
Cited by 49 | Viewed by 6893
Abstract
The latest investigations of long non-coding RNAs (lncRNAs) have revealed their important role in human cancers. LncRNAs are larger than 200 nucleotides in length and fulfill their cellular purpose without being translated into proteins. Though the molecular functions of some lncRNAs have been [...] Read more.
The latest investigations of long non-coding RNAs (lncRNAs) have revealed their important role in human cancers. LncRNAs are larger than 200 nucleotides in length and fulfill their cellular purpose without being translated into proteins. Though the molecular functions of some lncRNAs have been elucidated, there is still a high number of lncRNAs with unknown or controversial functions. In this review, we provide an overview of different lncRNAs and their role in human cancers. In particular, we emphasize their importance in tumorigenesis of colorectal cancer, the third most common cancer worldwide. Full article
Show Figures

Figure 1

743 KiB  
Review
Non-Coding RNAs and Lipid Metabolism
by Elisabeth Smolle and Johannes Haybaeck
Int. J. Mol. Sci. 2014, 15(8), 13494-13513; https://doi.org/10.3390/ijms150813494 - 04 Aug 2014
Cited by 26 | Viewed by 6239
Abstract
A high percentage of the mammalian genome consists of non-coding RNAs (ncRNAs). Among ncRNAs two main subgroups have been identified: long ncRNAs (lncRNAs) and micro RNAs (miRNAs). ncRNAs have been demonstrated to play a role in a vast variety of diseases, since they [...] Read more.
A high percentage of the mammalian genome consists of non-coding RNAs (ncRNAs). Among ncRNAs two main subgroups have been identified: long ncRNAs (lncRNAs) and micro RNAs (miRNAs). ncRNAs have been demonstrated to play a role in a vast variety of diseases, since they regulate gene transcription and are involved in post-transcriptional regulation. They have the potential to function as molecular signals or as guides for transcription factors and to regulate epigenetic modifiers. In this literature review we have summarized data on miRNAs and lncRNAs and their involvement in dyslipidaemia, atherosclerosis, insulin resistance and adipogenesis. Outlining certain ncRNAs as disease biomarkers and/or therapeutic targets, and testing them in vivo, will be the next steps in future research. Full article
Back to TopTop