International Journal of Molecular Sciences

2024

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18 pages, 2270 KiB

Open AccessReview

An In-Depth Approach to the Associations between MicroRNAs and Viral Load in Patients with Chronic Hepatitis B—A Systematic Review and Meta-Analysis

by Marina Manea, Ion Mărunțelu and Ileana Constantinescu

Int. J. Mol. Sci. 2024, 25(15), 8410; https://doi.org/10.3390/ijms25158410 - 1 Aug 2024

Viewed by 632

Abstract

Scientists study the molecular activities of the hepatitis B virus (HBV). However, in vivo experiments are scarce. Some microRNAs are HBV-related, but their exact mechanisms are unknown. Our study provides an up-to-date view of the associations between microRNAs and HBV-DNA levels in chronically [...] Read more.

Scientists study the molecular activities of the hepatitis B virus (HBV). However, in vivo experiments are scarce. Some microRNAs are HBV-related, but their exact mechanisms are unknown. Our study provides an up-to-date view of the associations between microRNAs and HBV-DNA levels in chronically infected individuals. We conducted this large-scale research on five databases according to PRISMA guidance. Joanna Briggs Institute tools and Newcastle Ottawa Quality Assessment scores helped with quality evaluations. R 4.2.2 performed statistical computations for the meta-analysis. DIANA-microT 2023 and g:Profiler enriched the predictions of liver genes associated with miR-122 and miR-192-5p. From the 1313 records, we eliminated those irrelevant to our theme, non-article methodologies, non-English entries, and duplicates. We assessed associations between microRNAs and HBV-DNA levels. Overall, the pooled correlations favoured the general idea of the connection between non-coding molecules and viremia levels. MiR-122 and miR-192-5p were the most researched microRNAs, significantly associated with HBV-DNA levels. The connections between miR-122, miR-192-5p, let-7, miR-215, miR-320, and viral loads need further in vivo assessment. To conclude, this study evaluates systematically, for the first time, the correlations between non-coding molecules and viremia levels in patients. Our meta-analysis emphasizes potentially important pathways toward new inhibitors of the viral replication cycle. Full article

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2023

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20 pages, 20046 KiB

Open AccessArticle

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 2 | Viewed by 1433

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

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22 pages, 3799 KiB

Open AccessArticle

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 - 4 Sep 2023

Cited by 1 | Viewed by 1465

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

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13 pages, 2636 KiB

Open AccessArticle

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 3 | Viewed by 2147

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

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20 pages, 901 KiB

Open AccessReview

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 15 | Viewed by 3477

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

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16 pages, 5573 KiB

Open AccessArticle

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 - 2 Mar 2023

Cited by 1 | Viewed by 1986

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

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15 pages, 2978 KiB

Open AccessArticle

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 - 9 Feb 2023

Cited by 5 | Viewed by 1835

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

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2022

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30 pages, 1617 KiB

Open AccessReview

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 13 | Viewed by 2999

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

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20 pages, 3081 KiB

Open AccessReview

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 4615

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

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19 pages, 1594 KiB

Open AccessReview

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 8 | Viewed by 3669

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

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20 pages, 1302 KiB

Open AccessReview

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 4 | Viewed by 2605

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

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12 pages, 1036 KiB

Open AccessReview

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 8 | Viewed by 2289

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

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14 pages, 2212 KiB

Open AccessArticle

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 1812

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

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21 pages, 3546 KiB

Open AccessArticle

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 9 | Viewed by 2718

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

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17 pages, 3890 KiB

Open AccessArticle

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 7 | Viewed by 2531

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

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23 pages, 2342 KiB

Open AccessReview

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 - 5 Jul 2022

Cited by 27 | Viewed by 5373

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

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13 pages, 4263 KiB

Open AccessArticle

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

Cited by 1 | Viewed by 1579

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

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18 pages, 2969 KiB

Open AccessReview

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 24 | Viewed by 3278

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

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32 pages, 28001 KiB

Open AccessArticle

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 4 | Viewed by 3191

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

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14 pages, 2293 KiB

Open AccessArticle

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 - 6 Jun 2022

Cited by 9 | Viewed by 2474

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

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11 pages, 900 KiB

Open AccessReview

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 - 2 Jun 2022

Cited by 21 | Viewed by 4031

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

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15 pages, 3066 KiB

Open AccessArticle

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 7 | Viewed by 2434

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

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32 pages, 3437 KiB

Open AccessReview

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 15 | Viewed by 2871

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

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35 pages, 2471 KiB

Open AccessReview

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 40 | Viewed by 6754

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

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14 pages, 1396 KiB

Open AccessArticle

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 8 | Viewed by 2006

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

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10 pages, 797 KiB

Open AccessReview

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 2357

Abstract

TRUE gene silencing is an RNA-mediated gene expression control technology and is termed after tRNase Z^L-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 Z^L-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 Z^L and cellular small RNA, and then sgRNA and TRUE gene silencing. An endoribonuclease, tRNase Z^L, 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 Z^L for gene regulation together with these small RNAs. By utilizing the property of tRNase Z^L to recognize and cleave micro-pre-tRNA, a pre-tRNA-like or micro-pre-tRNA-like complex, as well as pre-tRNA, tRNase Z^L 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

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15 pages, 796 KiB

Open AccessReview

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 - 8 May 2022

Cited by 7 | Viewed by 3127

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

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14 pages, 2557 KiB

Open AccessArticle

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 - 4 May 2022

Cited by 2 | Viewed by 2375

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

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15 pages, 3720 KiB

Open AccessArticle

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 2041

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

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2021

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16 pages, 5878 KiB

Open AccessArticle

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 6 | Viewed by 2952

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

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2020

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13 pages, 1087 KiB

Open AccessReview

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 13 | Viewed by 4524

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

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19 pages, 1475 KiB

Open AccessReview

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 22 | Viewed by 4246

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

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12 pages, 1378 KiB

Open AccessArticle

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 5 | Viewed by 2985

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

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2019

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18 pages, 1732 KiB

Open AccessReview

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 60 | Viewed by 4202

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

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29 pages, 3124 KiB

Open AccessReview

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 - 8 Nov 2019

Cited by 521 | Viewed by 15247

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

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27 pages, 1211 KiB

Open AccessReview

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 - 6 Oct 2019

Cited by 228 | Viewed by 19126

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

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12 pages, 2223 KiB

Open AccessArticle

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 26 | Viewed by 7830

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

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20 pages, 418 KiB

Open AccessReview

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 70 | Viewed by 5496

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

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13 pages, 2192 KiB

Open AccessArticle

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 - 3 Apr 2019

Cited by 12 | Viewed by 3611

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

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11 pages, 2382 KiB

Open AccessArticle

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 16 | Viewed by 4042

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

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16 pages, 4940 KiB

Open AccessArticle

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 30 | Viewed by 3504

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

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17 pages, 1475 KiB

Open AccessReview

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 - 1 Feb 2019

Cited by 75 | Viewed by 8392

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

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22 pages, 5783 KiB

Open AccessArticle

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 51 | Viewed by 5591

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

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2018

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11 pages, 1290 KiB

Open AccessArticle

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 45 | Viewed by 4546

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

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17 pages, 2048 KiB

Open AccessArticle

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 - 8 Oct 2018

Cited by 24 | Viewed by 4556

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

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11 pages, 2868 KiB

Open AccessArticle

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 15 | Viewed by 4170

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

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15 pages, 1353 KiB

Open AccessReview

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 4507

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

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12 pages, 450 KiB

Open AccessReview

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 46 | Viewed by 8005

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

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13 pages, 5149 KiB

Open AccessArticle

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 59 | Viewed by 4766

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

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15 pages, 2943 KiB

Open AccessArticle

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 59 | Viewed by 5520

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

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11 pages, 2665 KiB

Open AccessArticle

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 - 4 May 2018

Cited by 4 | Viewed by 4413

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

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4 pages, 506 KiB

Open AccessCorrection

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 - 2 May 2018

Cited by 1 | Viewed by 3278

Abstract

n/a Full article

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14 pages, 2934 KiB

Open AccessArticle

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 23 | Viewed by 6473

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

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15 pages, 7494 KiB

Open AccessArticle

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 6626

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

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23 pages, 1998 KiB

Open AccessReview

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 - 8 Feb 2018

Cited by 67 | Viewed by 11561

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

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15 pages, 665 KiB

Open AccessReview

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 32 | Viewed by 9085

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

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23 pages, 1957 KiB

Open AccessReview

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 - 2 Jan 2018

Cited by 62 | Viewed by 7704

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

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Open AccessArticle

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 36 | Viewed by 7238

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

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Open AccessReview

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 170 | Viewed by 11090

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

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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 57 | Viewed by 8799

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

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3788 KiB

Open AccessArticle

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 37 | Viewed by 6430

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

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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 32 | Viewed by 6715

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)

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