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Topical Collection "Regulation by Non-Coding RNAs"

Editor

Collection Editor
Dr. Martin Pichler *

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

Topical Collection Information

Dear Colleagues,

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

Dr. Martin Pichler
Collection Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The article processing charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs).

Keywords

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

Related Special Issues

Published Papers (116 papers)

2018

Jump to: 2017, 2016, 2015, 2014

Open AccessArticle The Novel miRNA N-72 Regulates EGF-Induced Migration of Human Amnion Mesenchymal Stem Cells by Targeting MMP2
Int. J. Mol. Sci. 2018, 19(5), 1363; https://doi.org/10.3390/ijms19051363
Received: 9 April 2018 / Revised: 28 April 2018 / Accepted: 2 May 2018 / Published: 4 May 2018
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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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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
Int. J. Mol. Sci. 2018, 19(5), 1343; https://doi.org/10.3390/ijms19051343
Received: 10 April 2018 / Revised: 11 April 2018 / Accepted: 12 April 2018 / Published: 2 May 2018
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Open AccessArticle Organ-Specific MicroRNAs (MIR122, 137, and 206) Contribute to Tissue Characteristics and Carcinogenesis by Regulating Pyruvate Kinase M1/2 (PKM) Expression
Int. J. Mol. Sci. 2018, 19(5), 1276; https://doi.org/10.3390/ijms19051276
Received: 1 April 2018 / Revised: 16 April 2018 / Accepted: 18 April 2018 / Published: 24 April 2018
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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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Open AccessArticle Hippocampal MicroRNAs Respond to Administration of Antidepressant Fluoxetine in Adult Mice
Int. J. Mol. Sci. 2018, 19(3), 671; https://doi.org/10.3390/ijms19030671
Received: 25 January 2018 / Revised: 23 February 2018 / Accepted: 24 February 2018 / Published: 27 February 2018
PDF Full-text (7494 KB) | HTML Full-text | XML Full-text | Supplementary Files
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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Open AccessReview Plant Responses to Pathogen Attack: Small RNAs in Focus
Int. J. Mol. Sci. 2018, 19(2), 515; https://doi.org/10.3390/ijms19020515
Received: 26 December 2017 / Revised: 4 February 2018 / Accepted: 5 February 2018 / Published: 8 February 2018
Cited by 4 | PDF Full-text (1998 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Regulatory Role of MicroRNAs in Muscle Atrophy during Exercise Intervention
Int. J. Mol. Sci. 2018, 19(2), 405; https://doi.org/10.3390/ijms19020405
Received: 3 January 2018 / Revised: 26 January 2018 / Accepted: 27 January 2018 / Published: 30 January 2018
Cited by 1 | PDF Full-text (665 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Natural Antisense Transcripts: Molecular Mechanisms and Implications in Breast Cancers
Int. J. Mol. Sci. 2018, 19(1), 123; https://doi.org/10.3390/ijms19010123
Received: 13 October 2017 / Revised: 7 December 2017 / Accepted: 29 December 2017 / Published: 2 January 2018
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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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2017

Jump to: 2018, 2016, 2015, 2014

Open AccessArticle Integrated MicroRNA–mRNA Analysis Reveals miR-204 Inhibits Cell Proliferation in Gastric Cancer by Targeting CKS1B, CXCL1 and GPRC5A
Int. J. Mol. Sci. 2018, 19(1), 87; https://doi.org/10.3390/ijms19010087
Received: 16 November 2017 / Revised: 23 December 2017 / Accepted: 25 December 2017 / Published: 28 December 2017
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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
Int. J. Mol. Sci. 2017, 18(12), 2698; https://doi.org/10.3390/ijms18122698
Received: 28 September 2017 / Revised: 7 December 2017 / Accepted: 9 December 2017 / Published: 13 December 2017
Cited by 1 | PDF Full-text (1011 KB) | HTML Full-text | XML Full-text | Supplementary Files
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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Open AccessReview Long Non-Coding RNAs in Metabolic Organs and Energy Homeostasis
Int. J. Mol. Sci. 2017, 18(12), 2578; https://doi.org/10.3390/ijms18122578
Received: 13 October 2017 / Revised: 20 November 2017 / Accepted: 24 November 2017 / Published: 30 November 2017
Cited by 4 | PDF Full-text (707 KB) | HTML Full-text | XML Full-text
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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Open AccessArticle BCL11A mRNA Targeting by miR-210: A Possible Network Regulating γ-Globin Gene Expression
Int. J. Mol. Sci. 2017, 18(12), 2530; https://doi.org/10.3390/ijms18122530
Received: 23 October 2017 / Revised: 16 November 2017 / Accepted: 22 November 2017 / Published: 26 November 2017
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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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Open AccessReview Long Non-Coding RNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Regulation, Functions, and Underlying Mechanisms
Int. J. Mol. Sci. 2017, 18(12), 2505; https://doi.org/10.3390/ijms18122505
Received: 27 September 2017 / Revised: 13 November 2017 / Accepted: 20 November 2017 / Published: 23 November 2017
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Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death in the world. Hepatitis B virus (HBV) and its X gene-encoded protein (HBx) play important roles in the progression of HCC. Although long non-coding RNAs (lncRNAs)
[...] Read more.
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death in the world. Hepatitis B virus (HBV) and its X gene-encoded protein (HBx) play important roles in the progression of HCC. Although long non-coding RNAs (lncRNAs) cannot encode proteins, growing evidence indicates that they play essential roles in HCC progression, and contribute to cell proliferation, invasion and metastasis, autophagy, and apoptosis by targeting a large number of pivotal protein-coding genes, miRNAs, and signaling pathways. In this review, we briefly outline recent findings of differentially expressed lncRNAs in HBV-related HCC, with particular focus on several key lncRNAs, and discuss their regulation by HBV/HBx, their functions, and their underlying molecular mechanisms in the progression of HCC. Full article
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Open AccessReview MicroRNAs Associated with Von Hippel–Lindau Pathway in Renal Cell Carcinoma: A Comprehensive Review
Int. J. Mol. Sci. 2017, 18(11), 2495; https://doi.org/10.3390/ijms18112495
Received: 11 October 2017 / Revised: 7 November 2017 / Accepted: 17 November 2017 / Published: 22 November 2017
Cited by 2 | PDF Full-text (780 KB) | HTML Full-text | XML Full-text
Abstract
Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the
[...] Read more.
Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired resistance towards therapeutic agents over time. The discovery of microRNAs (miRNAs), a class of small, non-coding, single-stranded RNAs that play a crucial role in post-transcriptional regulation, has added new dimensions to the development of novel diagnostic and treatment tools. Because of an association between Von Hippel–Lindau (VHL) genes with chromosomal loss in 3p25-26 and clear cell RCC, miRNAs have attracted considerable scientific interest over the last years. The loss of VHL function leads to constitutional activation of the hypoxia inducible factor (HIF) pathway and to consequent expression of numerous angiogenic and carcinogenic factors. Since miRNAs represent key players of carcinogenesis, tumor cell invasion, angiogenesis, as well as in development of metastases in RCC, they might serve as potential therapeutic targets. Several miRNAs are already known to be dysregulated in RCC and have been linked to biological processes involved in tumor angiogenesis and response to anti-cancer therapies. This review summarizes the role of different miRNAs in RCC angiogenesis and their association with the VHL gene, highlighting their potential role as novel drug targets. Full article
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Open AccessReview The Dark Side of the Epitranscriptome: Chemical Modifications in Long Non-Coding RNAs
Int. J. Mol. Sci. 2017, 18(11), 2387; https://doi.org/10.3390/ijms18112387
Received: 1 October 2017 / Revised: 5 November 2017 / Accepted: 6 November 2017 / Published: 10 November 2017
Cited by 2 | PDF Full-text (1148 KB) | HTML Full-text | XML Full-text
Abstract
The broad application of next-generation sequencing technologies in conjunction with improved bioinformatics has helped to illuminate the complexity of the transcriptome, both in terms of quantity and variety. In humans, 70–90% of the genome is transcribed, but only ~2% carries the blueprint for
[...] Read more.
The broad application of next-generation sequencing technologies in conjunction with improved bioinformatics has helped to illuminate the complexity of the transcriptome, both in terms of quantity and variety. In humans, 70–90% of the genome is transcribed, but only ~2% carries the blueprint for proteins. Hence, there is a huge class of non-translated transcripts, called long non-coding RNAs (lncRNAs), which have received much attention in the past decade. Several studies have shown that lncRNAs are involved in a plethora of cellular signaling pathways and actively regulate gene expression via a broad selection of molecular mechanisms. Only recently, sequencing-based, transcriptome-wide studies have characterized different types of post-transcriptional chemical modifications of RNAs. These modifications have been shown to affect the fate of RNA and further expand the variety of the transcriptome. However, our understanding of their biological function, especially in the context of lncRNAs, is still in its infancy. In this review, we will focus on three epitranscriptomic marks, namely pseudouridine (Ψ), N6-methyladenosine (m6A) and 5-methylcytosine (m5C). We will introduce writers, readers, and erasers of these modifications, and we will present methods for their detection. Finally, we will provide insights into the distribution and function of these chemical modifications in selected, cancer-related lncRNAs. Full article
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Open AccessArticle Magnetic Beads-Based Sensor with Tailored Sensitivity for Rapid and Single-Step Amperometric Determination of miRNAs
Int. J. Mol. Sci. 2017, 18(11), 2151; https://doi.org/10.3390/ijms18112151
Received: 17 September 2017 / Revised: 8 October 2017 / Accepted: 9 October 2017 / Published: 9 November 2017
Cited by 4 | PDF Full-text (1798 KB) | HTML Full-text | XML Full-text
Abstract
This work describes a sensitive amperometric magneto-biosensor for single-step and rapid determination of microRNAs (miRNAs). The developed strategy involves the use of direct hybridization of the target miRNA (miRNA-21) with a specific biotinylated DNA probe immobilized on streptavidin-modified magnetic beads (MBs), and labeling
[...] Read more.
This work describes a sensitive amperometric magneto-biosensor for single-step and rapid determination of microRNAs (miRNAs). The developed strategy involves the use of direct hybridization of the target miRNA (miRNA-21) with a specific biotinylated DNA probe immobilized on streptavidin-modified magnetic beads (MBs), and labeling of the resulting heteroduplexes with a specific DNA–RNA antibody and the bacterial protein A (ProtA) conjugated with an horseradish peroxidase (HRP) homopolymer (Poly-HRP40) as an enzymatic label for signal amplification. Amperometric detection is performed upon magnetic capture of the modified MBs onto the working electrode surface of disposable screen-printed carbon electrodes (SPCEs) using the H2O2/hydroquinone (HQ) system. The magnitude of the cathodic signal obtained at −0.20 V (vs. the Ag pseudo-reference electrode) demonstrated linear dependence with the concentration of the synthetic target miRNA over the 1.0 to 100 pM range. The method provided a detection limit (LOD) of 10 attomoles (in a 25 μL sample) without any target miRNA amplification in just 30 min (once the DNA capture probe-MBs were prepared). This approach shows improved sensitivity compared with that of biosensors constructed with the same anti-DNA–RNA Ab as capture instead of a detector antibody and further labeling with a Strep-HRP conjugate instead of the Poly-HRP40 homopolymer. The developed strategy involves a single step working protocol, as well as the possibility to tailor the sensitivity by enlarging the length of the DNA/miRNA heteroduplexes using additional probes and/or performing the labelling with ProtA conjugated with homopolymers prepared with different numbers of HRP molecules. The practical usefulness was demonstrated by determination of the endogenous levels of the mature target miRNA in 250 ng raw total RNA (RNAt) extracted from human mammary epithelial normal (MCF-10A) and cancer (MCF-7) cells and tumor tissues. Full article
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Open AccessReview miRNAs, Melanoma and Microenvironment: An Intricate Network
Int. J. Mol. Sci. 2017, 18(11), 2354; https://doi.org/10.3390/ijms18112354
Received: 29 September 2017 / Revised: 2 November 2017 / Accepted: 5 November 2017 / Published: 7 November 2017
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Abstract
miRNAs are central players in cancer biology and they play a pivotal role in mediating the network communication between tumor cells and their microenvironment. In melanoma, miRNAs can impair or facilitate a wide array of processes, and here we will focus on: the
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miRNAs are central players in cancer biology and they play a pivotal role in mediating the network communication between tumor cells and their microenvironment. In melanoma, miRNAs can impair or facilitate a wide array of processes, and here we will focus on: the epithelial to mesenchymal transition (EMT), the immune milieu, and metabolism. Multiple miRNAs can affect the EMT process, even at a distance, for example through exosome-mediated mechanisms. miRNAs also strongly act on some components of the immune system, regulating the activity of key elements such as antigen presenting cells, and can facilitate an immune evasive/suppressive phenotype. miRNAs are also involved in the regulation of metabolic processes, specifically in response to hypoxic stimuli where they can mediate the metabolic switch from an oxidative to a glycolytic metabolism. Overall, this review discusses and summarizes recent findings on miRNA regulation in the melanoma tumor microenvironment, analyzing their potential diagnostic and therapeutic applications. Full article
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Open AccessReview Regulation of Human Breast Cancer by the Long Non-Coding RNA H19
Int. J. Mol. Sci. 2017, 18(11), 2319; https://doi.org/10.3390/ijms18112319
Received: 3 October 2017 / Revised: 27 October 2017 / Accepted: 30 October 2017 / Published: 3 November 2017
Cited by 4 | PDF Full-text (1465 KB) | HTML Full-text | XML Full-text
Abstract
Breast cancer is one of the most common causes of cancer related deaths in women. Despite the progress in early detection and use of new therapeutic targets associated with development of novel therapeutic options, breast cancer remains a major problem in public health.
[...] Read more.
Breast cancer is one of the most common causes of cancer related deaths in women. Despite the progress in early detection and use of new therapeutic targets associated with development of novel therapeutic options, breast cancer remains a major problem in public health. Indeed, even if the survival rate has improved for breast cancer patients, the number of recurrences within five years and the five-year relative survival rate in patients with metastasis remain dramatic. Thus, the discovery of new molecular actors involved in breast progression is essential to improve the management of this disease. Numerous data indicate that long non-coding RNA are implicated in breast cancer development. The oncofetal lncRNA H19 was the first RNA identified as a riboregulator. Studying of this lncRNA revealed its implication in both normal development and diseases. In this review, we summarize the different mechanisms of action of H19 in human breast cancer. Full article
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Open AccessReview To Wnt or Lose: The Missing Non-Coding Linc in Colorectal Cancer
Int. J. Mol. Sci. 2017, 18(9), 2003; https://doi.org/10.3390/ijms18092003
Received: 9 August 2017 / Revised: 9 September 2017 / Accepted: 13 September 2017 / Published: 20 September 2017
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Abstract
Colorectal cancer (CRC) is the third most frequent cancer and one of the leading causes for cancer-related mortality. Aberrant activation of the Wnt signaling is an essential initiating factor in colon carcinogenesis, and a driving force of CRC progression. Recently, long non-coding RNAs
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Colorectal cancer (CRC) is the third most frequent cancer and one of the leading causes for cancer-related mortality. Aberrant activation of the Wnt signaling is an essential initiating factor in colon carcinogenesis, and a driving force of CRC progression. Recently, long non-coding RNAs (lncRNAs) have emerged as significant players in CRC pathogenesis through diversified mechanisms. Although both Wnt signaling and lncRNAs represent interesting research areas for CRC, an effort of directly connecting these two areas is lacking. To fill in the knowledge gap, we focus on the reported findings of lncRNAs that regulate Wnt signaling or essential Wnt signaling targets. These include several newly discovered lncRNAs originated from the amplified cancer-associated chromosome 8q24 region that surrounds the essential Wnt target MYC gene, lncRNAs reported to be involved in CRC stem cells, and several individual lncRNAs connected to Wnt signaling through other mechanisms. This review will provide essential information that assists in understanding the missing link of lncRNAs to the classical Wnt signaling in CRC. Full article
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Open AccessReview MicroRNAs in Different Histologies of Soft Tissue Sarcoma: A Comprehensive Review
Int. J. Mol. Sci. 2017, 18(9), 1960; https://doi.org/10.3390/ijms18091960
Received: 5 September 2017 / Revised: 7 September 2017 / Accepted: 8 September 2017 / Published: 12 September 2017
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Abstract
Soft tissue sarcomas (STS) constitute a rare tumour entity comprising over 50 histological subtypes. MicroRNAs (miRNAs) are short non-protein coding RNA molecules that regulate gene expression by targeting the 3’-untranslated region of messenger RNAs. They are involved in a variety of human diseases,
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Soft tissue sarcomas (STS) constitute a rare tumour entity comprising over 50 histological subtypes. MicroRNAs (miRNAs) are short non-protein coding RNA molecules that regulate gene expression by targeting the 3’-untranslated region of messenger RNAs. They are involved in a variety of human diseases, including malignancies, such as endometrial cancer, osteosarcoma, bronchial carcinoma and breast cancer. In STS, various miRNAs are differentially expressed, thus contributing to development, progression and invasion. Therefore, the aim of the present review is to summarise current knowledge on the role of miRNAs in STS. Furthermore, the potential role of miRNAs as diagnostic, prognostic and predictive biomarkers is discussed. Full article
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Open AccessArticle MiR-30a-5p Inhibits Epithelial-to-Mesenchymal Transition and Upregulates Expression of Tight Junction Protein Claudin-5 in Human Upper Tract Urothelial Carcinoma Cells
Int. J. Mol. Sci. 2017, 18(8), 1826; https://doi.org/10.3390/ijms18081826
Received: 13 July 2017 / Revised: 14 August 2017 / Accepted: 18 August 2017 / Published: 22 August 2017
Cited by 1 | PDF Full-text (17895 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The involvement of microRNAs (miRNAs) in cancer development and their potential as prognostic biomarkers are becoming increasingly known. However, the signature of miRNAs and their regulatory roles in tumorigenesis of upper tract urothelial carcinoma (UTUC) remain to be elucidated. This study aimed to
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The involvement of microRNAs (miRNAs) in cancer development and their potential as prognostic biomarkers are becoming increasingly known. However, the signature of miRNAs and their regulatory roles in tumorigenesis of upper tract urothelial carcinoma (UTUC) remain to be elucidated. This study aimed to profile the miRNA expression pattern in UTUC tumor tissues and identify candidate miRNAs with prognostic and/or therapeutic functions. Methods and Results: We collected 22 UTUC tissue and adjacent normal tissues samples from patients who underwent nephroureterectomy. The miRNAs signatures of three selected UTUC samples using next-generation sequencing showed that miR-30a-5p was significantly downregulated in UTUC tumors compared to adjacent normal tissues. The differentially-expressed miRNAs were specifically validated by quantitative real-time polymerase chain reaction. In addition, the miRNA expression signatures were analyzed with the transcriptome profile characterized by microarray. Further in vitro studies indicated that overexpression of miR-30a-5p significantly suppressed proliferation, migration, and epithelial-to-mesenchymal transition (EMT) in cultured BFTC-909 UTUC cells. As a potential target gene of miR-30a-5p in the tight junction pathway suggested by the pathway enrichment analysis, the reduced expression of tight junction protein claudin-5 in UTUC cells was demonstrated to be upregulated by miR-30a-5p genetic delivery. Conclusions: Taken together, our findings demonstrated that miR-30a-5p inhibits proliferation, metastasis, and EMT, and upregulates the expression of tight junction claudin-5 in UTUC cells. Thus, miR-30a-5p may provide a promising therapeutic strategy for UTUC treatment. Full article
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Open AccessArticle Differential miR-346 and miR-582-3p Expression in Association with Selected Maternal and Fetal Complications
Int. J. Mol. Sci. 2017, 18(7), 1570; https://doi.org/10.3390/ijms18071570
Received: 12 May 2017 / Revised: 27 June 2017 / Accepted: 10 July 2017 / Published: 19 July 2017
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Abstract
Several miRNAs are expressed in human gestational tissue, and some have been shown to be associated with placental dysfunction and complicated pregnancy outcomes. To investigate the roles of miR-346 and miR-582-3p in adverse obstetric events, we analyzed these 2 miRNAs in three samples
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Several miRNAs are expressed in human gestational tissue, and some have been shown to be associated with placental dysfunction and complicated pregnancy outcomes. To investigate the roles of miR-346 and miR-582-3p in adverse obstetric events, we analyzed these 2 miRNAs in three samples (maternal blood, umbilical cord blood and placenta) obtained from pregnant women in four groups, including healthy control (n = 60), preeclampsia (n = 31), preterm delivery (n = 29) and small for gestational age (n = 19) patients. The expression levels of miR-346 and miR-582-3p in all included adverse obstetric outcome groups were significantly higher in the maternal plasma samples but lower in the placenta samples (all p value < 0.05). In addition, the miR-346 expression levels in fetal cord blood were also significantly lower in all of the included adverse obstetric outcome groups (all p < 0.05). Multivariate analysis of the three specimens after adjusting for maternal age and gestational age at delivery gave the same results. In conclusion, aberrant miR-346 and miR-582-3p expression level in pregnancy was associated with multiple maternal and fetal complications. Their differential expression in maternal blood, umbilical cord blood and placenta could be potential biomarkers or therapeutic targets for adverse obstetric outcomes Full article
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Open AccessArticle Induction of miR-3648 Upon ER Stress and Its Regulatory Role in Cell Proliferation
Int. J. Mol. Sci. 2017, 18(7), 1375; https://doi.org/10.3390/ijms18071375
Received: 3 May 2017 / Revised: 20 June 2017 / Accepted: 22 June 2017 / Published: 29 June 2017
Cited by 4 | PDF Full-text (3861 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
MicroRNAs (miRNAs) play important roles under multiple cellular conditions including endoplasmic reticulum (ER) stress. We found that miR-3648, a human specific microRNA, was induced under ER stress. Moreover, Adenomatous polyposis coli 2 (APC2), a tumor suppressor and a negative regulator of Wnt signaling,
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MicroRNAs (miRNAs) play important roles under multiple cellular conditions including endoplasmic reticulum (ER) stress. We found that miR-3648, a human specific microRNA, was induced under ER stress. Moreover, Adenomatous polyposis coli 2 (APC2), a tumor suppressor and a negative regulator of Wnt signaling, was found to be the direct target of miR-3648. Levels of APC2 were downregulated when cells were under ER stress or after overexpressing miR-3648. Inhibition of miR-3648 by antagomir increased APC2 levels and decreased cell proliferation. Conversely, when miR-3648 was overexpressed, APC2 levels were decreased and the cell growth increased. Our data demonstrated that ER stress mediated induction of miR-3648 in human cells, which then downregulated APC2 to increase cell proliferation. Full article
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Open AccessArticle Multiple Isoforms of ANRIL in Melanoma Cells: Structural Complexity Suggests Variations in Processing
Int. J. Mol. Sci. 2017, 18(7), 1378; https://doi.org/10.3390/ijms18071378
Received: 27 May 2017 / Revised: 21 June 2017 / Accepted: 22 June 2017 / Published: 27 June 2017
Cited by 2 | PDF Full-text (1186 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The long non-coding RNA ANRIL, antisense to the CDKN2B locus, is transcribed from a gene that encompasses multiple disease-associated polymorphisms. Despite the identification of multiple isoforms of ANRIL, expression of certain transcripts has been found to be tissue-specific and the characterisation
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The long non-coding RNA ANRIL, antisense to the CDKN2B locus, is transcribed from a gene that encompasses multiple disease-associated polymorphisms. Despite the identification of multiple isoforms of ANRIL, expression of certain transcripts has been found to be tissue-specific and the characterisation of ANRIL transcripts remains incomplete. Several functions have been associated with ANRIL. In our judgement, studies on ANRIL functionality are premature pending a more complete appreciation of the profusion of isoforms. We found differential expression of ANRIL exons, which indicates that multiple isoforms exist in melanoma cells. In addition to linear isoforms, we identified circular forms of ANRIL (circANRIL). Further characterisation of circANRIL in two patient-derived metastatic melanoma cell lines (NZM7 and NZM37) revealed the existence of a rich assortment of circular isoforms. Moreover, in the two melanoma cell lines investigated, the complements of circANRIL isoforms were almost completely different. Novel exons were also discovered. We also found the family of linear ANRIL was enriched in the nucleus, whilst the circular isoforms were enriched in the cytoplasm and they differed markedly in stability. With respect to the variable processing of circANRIL species, bioinformatic analysis indicated that intronic Arthrobacter luteus (Alu) restriction endonuclease inverted repeats and exon skipping were not involved in selection of back-spliced exon junctions. Based on our findings, we hypothesise that “ANRIL” has wholly distinct dual sets of functions in melanoma. This reveals the dynamic nature of the locus and constitutes a basis for investigating the functions of ANRIL in melanoma. Full article
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Open AccessReview Mechanistic Insight into Long Noncoding RNAs and the Placenta
Int. J. Mol. Sci. 2017, 18(7), 1371; https://doi.org/10.3390/ijms18071371
Received: 17 May 2017 / Revised: 19 June 2017 / Accepted: 21 June 2017 / Published: 27 June 2017
Cited by 2 | PDF Full-text (923 KB) | HTML Full-text | XML Full-text
Abstract
Long non-coding RNAs (lncRNAs) are classified as RNAs greater than 200 nucleotides in length that do not produce a protein product. lncRNAs are expressed with cellular and temporal specificity and have been shown to play a role in many cellular events, including the
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Long non-coding RNAs (lncRNAs) are classified as RNAs greater than 200 nucleotides in length that do not produce a protein product. lncRNAs are expressed with cellular and temporal specificity and have been shown to play a role in many cellular events, including the regulation of gene expression, post-transcriptional modifications and epigenetic modifications. Since lncRNAs were first discovered, there has been increasing evidence that they play important roles in the development and function of most organs, including the placenta. The placenta is an essential transient organ that facilitates communication and nutrient exchange between the mother and foetus. The placenta is of foetal origin and begins to form shortly after the embryo implants into the uterine wall. The placenta relies heavily on the successful differentiation and function of trophoblast cells, including invasion as well as the formation of the maternal/foetal interface. Here, we review the current literature surrounding the involvement of lncRNAs in the development and function of trophoblasts and the human placenta. Full article
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Open AccessReview Micro-RNAs as Potential Predictors of Response to Breast Cancer Systemic Therapy: Future Clinical Implications
Int. J. Mol. Sci. 2017, 18(6), 1182; https://doi.org/10.3390/ijms18061182
Received: 21 April 2017 / Revised: 24 May 2017 / Accepted: 27 May 2017 / Published: 2 June 2017
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Abstract
Despite advances in diagnosis and new treatments such as targeted therapies, breast cancer (BC) is still the most prevalent tumor in women worldwide and the leading cause of death. The principal obstacle for successful BC treatment is the acquired or de novo resistance
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Despite advances in diagnosis and new treatments such as targeted therapies, breast cancer (BC) is still the most prevalent tumor in women worldwide and the leading cause of death. The principal obstacle for successful BC treatment is the acquired or de novo resistance of the tumors to the systemic therapy (chemotherapy, endocrine, and targeted therapies) that patients receive. In the era of personalized treatment, several studies have focused on the search for biomarkers capable of predicting the response to this therapy; microRNAs (miRNAs) stand out among these markers due to their broad spectrum or potential clinical applications. miRNAs are conserved small non-coding RNAs that act as negative regulators of gene expression playing an important role in several cellular processes, such as cell proliferation, autophagy, genomic stability, and apoptosis. We reviewed recent data that describe the role of miRNAs as potential predictors of response to systemic treatments in BC. Furthermore, upon analyzing the collected published information, we noticed that the overexpression of miR-155, miR-222, miR-125b, and miR-21 predicts the resistance to the most common systemic treatments; nonetheless, the function of these particular miRNAs must be carefully studied and further analyses are still necessary to increase knowledge about their role and future potential clinical uses in BC. Full article
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Open AccessReview Dietary Intervention by Phytochemicals and Their Role in Modulating Coding and Non-Coding Genes in Cancer
Int. J. Mol. Sci. 2017, 18(6), 1178; https://doi.org/10.3390/ijms18061178
Received: 21 April 2017 / Revised: 20 May 2017 / Accepted: 24 May 2017 / Published: 1 June 2017
Cited by 6 | PDF Full-text (2360 KB) | HTML Full-text | XML Full-text
Abstract
Phytochemicals are natural compounds synthesized as secondary metabolites in plants, representing an important source of molecules with a wide range of therapeutic applications. These natural agents are important regulators of key pathological processes/conditions, including cancer, as they are able to modulate the expression
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Phytochemicals are natural compounds synthesized as secondary metabolites in plants, representing an important source of molecules with a wide range of therapeutic applications. These natural agents are important regulators of key pathological processes/conditions, including cancer, as they are able to modulate the expression of coding and non-coding transcripts with an oncogenic or tumour suppressor role. These natural agents are currently exploited for the development of therapeutic strategies alone or in tandem with conventional treatments for cancer. The aim of this paper is to review the recent studies regarding the role of these natural phytochemicals in different processes related to cancer inhibition, including apoptosis activation, angiogenesis and metastasis suppression. From the large palette of phytochemicals we selected epigallocatechin gallate (EGCG), caffeic acid phenethyl ester (CAPE), genistein, morin and kaempferol, due to their increased activity in modulating multiple coding and non-coding genes, targeting the main hallmarks of cancer. Full article
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Open AccessArticle Loss of BAX by miR-365 Promotes Cutaneous Squamous Cell Carcinoma Progression by Suppressing Apoptosis
Int. J. Mol. Sci. 2017, 18(6), 1157; https://doi.org/10.3390/ijms18061157
Received: 3 May 2017 / Revised: 3 May 2017 / Accepted: 26 May 2017 / Published: 30 May 2017
Cited by 3 | PDF Full-text (3136 KB) | HTML Full-text | XML Full-text
Abstract
Pro-apoptotic BCL2 associated X (BAX) is traditionally thought to be regulated by anti-apoptotic BCL-2 family members, like BCL2-like 1 (BCL-XL), at the protein level. However, the posttranscriptional regulation of BAX is under explored. In this study, we identified BAX as the novel downstream
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Pro-apoptotic BCL2 associated X (BAX) is traditionally thought to be regulated by anti-apoptotic BCL-2 family members, like BCL2-like 1 (BCL-XL), at the protein level. However, the posttranscriptional regulation of BAX is under explored. In this study, we identified BAX as the novel downstream target of miR-365, which is supported by gain- and loss-of-function studies of onco-miR-365. Loss of BAX by either RNA interference or highly-expressed miR-365 in cells of cutaneous squamous cell carcinoma (CSCC) enhanced the tumor resistance against apoptosis, while repressing cell proliferation, migration, and invasiveness. In vivo experiment confirmed that BAX knockdown promotes the growth of CSCC xenografts. Collectively, our results find a miR-365-BAX axis for alleviating the pro-apoptotic effects of BAX, which promotes CSCC development and may facilitate the generation of novel therapeutic regimens to the clinical treatment of CSCC. Full article
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Open AccessReview Non-Coding RNAs in Hodgkin Lymphoma
Int. J. Mol. Sci. 2017, 18(6), 1154; https://doi.org/10.3390/ijms18061154
Received: 4 May 2017 / Revised: 23 May 2017 / Accepted: 26 May 2017 / Published: 29 May 2017
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Abstract
MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression by binding to the 3’-UTR of their target genes, can act as oncogenes or tumor suppressors. Recently, other types of non-coding RNAs—piwiRNAs and long non-coding RNAs—have also been identified. Hodgkin lymphoma (HL) is a
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MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression by binding to the 3’-UTR of their target genes, can act as oncogenes or tumor suppressors. Recently, other types of non-coding RNAs—piwiRNAs and long non-coding RNAs—have also been identified. Hodgkin lymphoma (HL) is a B cell origin disease characterized by the presence of only 1% of tumor cells, known as Hodgkin and Reed-Stenberg (HRS) cells, which interact with the microenvironment to evade apoptosis. Several studies have reported specific miRNA signatures that can differentiate HL lymph nodes from reactive lymph nodes, identify histologic groups within classical HL, and distinguish HRS cells from germinal center B cells. Moreover, some signatures are associated with survival or response to chemotherapy. Most of the miRNAs in the signatures regulate genes related to apoptosis, cell cycle arrest, or signaling pathways. Here we review findings on miRNAs in HL, as well as on other non-coding RNAs. Full article
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Open AccessReview dFmr1 Plays Roles in Small RNA Pathways of Drosophila melanogaster
Int. J. Mol. Sci. 2017, 18(5), 1066; https://doi.org/10.3390/ijms18051066
Received: 1 March 2017 / Revised: 9 May 2017 / Accepted: 10 May 2017 / Published: 16 May 2017
Cited by 2 | PDF Full-text (1992 KB) | HTML Full-text | XML Full-text
Abstract
Fragile-X syndrome is the most common form of inherited mental retardation accompanied by other phenotypes, including macroorchidism. The disorder originates with mutations in the Fmr1 gene coding for the FMRP protein, which, with its paralogs FXR1 and FXR2, constitute a well-conserved family
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Fragile-X syndrome is the most common form of inherited mental retardation accompanied by other phenotypes, including macroorchidism. The disorder originates with mutations in the Fmr1 gene coding for the FMRP protein, which, with its paralogs FXR1 and FXR2, constitute a well-conserved family of RNA-binding proteins. Drosophila melanogaster is a good model for the syndrome because it has a unique fragile X-related gene: dFmr1. Recently, in addition to its confirmed role in the miRNA pathway, a function for dFmr1 in the piRNA pathway, operating in Drosophila gonads, has been established. In this review we report a summary of the piRNA pathways occurring in gonads with a special emphasis on the relationship between the piRNA genes and the crystal-Stellate system; we also analyze the roles of dFmr1 in the Drosophila gonads, exploring their genetic and biochemical interactions to reveal some unexpected connections. Full article
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Open AccessArticle Specific MicroRNA Pattern in Colon Tissue of Young Children with Eosinophilic Colitis
Int. J. Mol. Sci. 2017, 18(5), 1050; https://doi.org/10.3390/ijms18051050
Received: 14 March 2017 / Revised: 15 April 2017 / Accepted: 5 May 2017 / Published: 12 May 2017
PDF Full-text (2109 KB) | HTML Full-text | XML Full-text | Correction | Supplementary Files
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Eosinophilic colitis (EC) is a common cause of haematochezia in infants and young children. The exact pathomechanism is not understood, and the diagnosis is challenging. The role of microRNAs as key class of regulators of mRNA expression and translation in patients with EC
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Eosinophilic colitis (EC) is a common cause of haematochezia in infants and young children. The exact pathomechanism is not understood, and the diagnosis is challenging. The role of microRNAs as key class of regulators of mRNA expression and translation in patients with EC has not been explored. Therefore, the aim of the present study was to explore the miRNA profile in EC with respect to eosinophilic inflammation. Patients enrolled in the study (n = 10) had persistent rectal bleeding, and did not respond to elimination dietary treatment. High-throughput microRNA sequencing was carried out on colonic biopsy specimens of children with EC (EC: n = 4) and controls (C: n = 4) as a preliminary screening of the miRNA profile. Based on the next-generation sequencing (NGS) results and literature data, a potentially relevant panel of miRNAs were selected for further measurements by real-time reverse transcription (RT)-PCR (EC: n = 14, C: n = 10). Validation by RT-PCR resulted in significantly altered expression of miR-21, -31, -99b, -125a, -146a, -184, -221, -223, and -559 compared to controls (p ≤ 0.05). Elevation in miR-21, -99b, -146a, -221, and -223 showed statistically significant correlation to the extent of tissue eosinophilia. Based on our results, we conclude that the dysregulated miRNAs have a potential role in the regulation of apoptosis by targeting Protein kinase B/Mechanistic target of rapamycin (AKT/mTOR)-related pathways in inflammation by modulating Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related signalling and eosinophil cell recruitment and activation, mainly by regulating the expression of the chemoattractant eotaxin and the adhesion molecule CD44. Our results could serve as a basis for further extended research exploring the pathomechanism of EC. Full article
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Open AccessArticle miR-365 Ameliorates Dexamethasone-Induced Suppression of Osteogenesis in MC3T3-E1 Cells by Targeting HDAC4
Int. J. Mol. Sci. 2017, 18(5), 977; https://doi.org/10.3390/ijms18050977
Received: 4 April 2017 / Revised: 27 April 2017 / Accepted: 28 April 2017 / Published: 4 May 2017
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Glucocorticoid administration is the leading cause of secondary osteoporosis. In this study, we tested the hypotheses that histone deacetylase 4 (HDAC4) is associated with glucocorticoid-induced bone loss and that HDAC4 dependent bone loss can be ameliorated by miRNA-365. Our previous studies showed that
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Glucocorticoid administration is the leading cause of secondary osteoporosis. In this study, we tested the hypotheses that histone deacetylase 4 (HDAC4) is associated with glucocorticoid-induced bone loss and that HDAC4 dependent bone loss can be ameliorated by miRNA-365. Our previous studies showed that miR-365 mediates mechanical stimulation of chondrocyte proliferation and differentiation by targeting HDAC4. However, it is not clear whether miR-365 has an effect on glucocorticoid-induced osteoporosis. We have shown that, in MC3T3-E1 osteoblasts, dexamethasone (DEX) treatment decreased the expression of miR-365, which is accompanied by the decrease of cell viability in a dose-dependent manner. Transfection of miR-365 ameliorated DEX-induced inhibition of MC3T3-E1 cell viability and alkaline phosphatase activity, and attenuated the suppressive effect of DEX on runt-related transcription factor 2 (Runx2), osteopontin (OPN), and collagen 1a1 (Col1a1) osteogenic gene expression. In addition, miR-365 decreased the expression of HDAC4 mRNA and protein by direct targeting the 3′-untranslated regions (3′-UTR) of HDAC4 mRNA in osteoblasts. MiR-365 increased Runx2 expression and such stimulatory effect could be reversed by HDAC4 over-expression in osteoblasts. Collectively, our findings indicate that miR-365 ameliorates DEX-induced suppression of cell viability and osteogenesis by regulating the expression of HDAC4 in osteoblasts, suggesting miR-365 might be a novel therapeutic agent for treatment of glucocorticoid-induced osteoporosis. Full article
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Open AccessReview Small RNA Pathways That Protect the Somatic Genome
Int. J. Mol. Sci. 2017, 18(5), 912; https://doi.org/10.3390/ijms18050912
Received: 7 April 2017 / Revised: 21 April 2017 / Accepted: 24 April 2017 / Published: 26 April 2017
Cited by 2 | PDF Full-text (1860 KB) | HTML Full-text | XML Full-text
Abstract
Transposable elements (TEs) are DNA elements that can change their position within the genome, with the potential to create mutations and destabilize the genome. As such, special molecular systems have been adopted in animals to control TE activity in order to protect the
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Transposable elements (TEs) are DNA elements that can change their position within the genome, with the potential to create mutations and destabilize the genome. As such, special molecular systems have been adopted in animals to control TE activity in order to protect the genome. PIWI proteins, in collaboration with PIWI-interacting RNAs (piRNAs), are well known to play a critical role in silencing germline TEs. Although initially thought to be germline-specific, the role of PIWI–piRNA pathways in controlling TEs in somatic cells has recently begun to be explored in various organisms, together with the role of endogenous small interfering RNAs (endo-siRNAs). This review summarizes recent results suggesting that these small RNA pathways have been critically implicated in the silencing of somatic TEs underlying various physiological traits, with a special focus on the Drosophila model organism. Full article
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Open AccessReview Regulatory miRNAs in Colorectal Carcinogenesis and Metastasis
Int. J. Mol. Sci. 2017, 18(4), 890; https://doi.org/10.3390/ijms18040890
Received: 30 March 2017 / Revised: 15 April 2017 / Accepted: 20 April 2017 / Published: 22 April 2017
Cited by 5 | PDF Full-text (520 KB) | HTML Full-text | XML Full-text
Abstract
Colorectal cancer is one of the most common malignancies and is the second-leading cause of cancer-related death world-wide, which is linked to genetic mutations, epigenetic alterations, and oncogenic signaling activation. MicroRNAs, one of the categories of epigenetics, have been demonstrated significant roles in
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Colorectal cancer is one of the most common malignancies and is the second-leading cause of cancer-related death world-wide, which is linked to genetic mutations, epigenetic alterations, and oncogenic signaling activation. MicroRNAs, one of the categories of epigenetics, have been demonstrated significant roles in carcinogenesis and progression through regulating of oncogenic signaling pathways, stem cells, epithelial-mesenchymal transition, and metastasis. This review summarizes the roles of microRNAs in the regulating of Wnt, Ras, TGF-β, and inflammatory signaling pathways, stemness, and epithelial-mesenchymal transition, for carcinogenesis and metastasis in colorectal cancer. Improving our understanding of the mechanisms of regulatory interactions of microRNAs with signaling pathways in colorectal cancer formation and progression will aid in determining the genes responsible for colorectal cancer initiation, progression, metastasis, and recurrence and, finally, in developing personalized approaches for cancer prevention and therapy. Full article
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Open AccessArticle Long Coding RNA XIST Contributes to Neuronal Apoptosis through the Downregulation of AKT Phosphorylation and Is Negatively Regulated by miR-494 in Rat Spinal Cord Injury
Int. J. Mol. Sci. 2017, 18(4), 732; https://doi.org/10.3390/ijms18040732
Received: 9 February 2017 / Revised: 17 March 2017 / Accepted: 22 March 2017 / Published: 1 April 2017
Cited by 8 | PDF Full-text (4780 KB) | HTML Full-text | XML Full-text
Abstract
Recent evidence has suggested that long non-coding RNAs (lncRNAs) may play a significant role in the pathogenesis of several neurological diseases, including spinal cord injury (SCI). However, little is known about the role of lncRNAs in SCI. The aim of the present study
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Recent evidence has suggested that long non-coding RNAs (lncRNAs) may play a significant role in the pathogenesis of several neurological diseases, including spinal cord injury (SCI). However, little is known about the role of lncRNAs in SCI. The aim of the present study was to evaluate the potential functions of lncRNAs in SCI and to identify the underlying mechanisms of action. We firstly analyzed Gene Expression Omnibus (GEO) datasets to investigate aberrantly-expressed lncRNAs which might be involved in the pathogenesis of SCI. The long non-coding RNA X-inactive specific transcript (XIST) was found to be one of the most significantly upregulated lncRNAs in the GEO dataset analysis, and is associated with apoptosis. We, therefore, selected this as a candidate lncRNA and investigated its function. We found that knockdown of lncRNA-XIST by Lv-shRNA had a prominent protective effect on SCI recovery by suppressing apoptosis through reactivation of the PI3K/AKT signaling pathway in rat spinal cord tissue. In particular, our results suggested that lncRNA-XIST may act as a competitive endogenous RNA, effectively becoming a sink for miR-494, leading to derepression of its target gene, phosphatase and tensin homolog deleted on chromosome ten (PTEN). In addition, an inverse relationship between lncRNA-XIST and miR-494 was observed in spinal cord tissues of SCI rats. Further study demonstrated that antagomiR-494 could reverse the protective effects of lncRNA-XIST knockdown on SCI rats through blocking the PTEN/PI3K/AKT signaling pathway. These results suggested that lncRNA-XIST knockdown may play an important role in limiting neuronal apoptosis in rats following SCI, and that the observed protective effects of lncRNA-XIST knockdown might have been mediated by its regulation on the phosphorylation of AKT by competitively binding miR-494. These findings have revealed, for the first time, the importance of the XIST/miR-494/PTEN/AKT signaling axis in the pathogenesis of SCI and suggest that lncRNA-XIST may be a promising molecular target for SCI therapy. Full article
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Open AccessReview Potentials of Long Noncoding RNAs (LncRNAs) in Sarcoma: From Biomarkers to Therapeutic Targets
Int. J. Mol. Sci. 2017, 18(4), 731; https://doi.org/10.3390/ijms18040731
Received: 14 February 2017 / Revised: 19 March 2017 / Accepted: 23 March 2017 / Published: 29 March 2017
Cited by 4 | PDF Full-text (865 KB) | HTML Full-text | XML Full-text
Abstract
Sarcoma includes some of the most heterogeneous tumors, which make the diagnosis, prognosis and treatment of these rare yet diverse neoplasms especially challenging. Long noncoding RNAs (lncRNAs) are important regulators of cancer initiation and progression, which implies their potential as neoteric prognostic and
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Sarcoma includes some of the most heterogeneous tumors, which make the diagnosis, prognosis and treatment of these rare yet diverse neoplasms especially challenging. Long noncoding RNAs (lncRNAs) are important regulators of cancer initiation and progression, which implies their potential as neoteric prognostic and diagnostic markers in cancer, including sarcoma. A relationship between lncRNAs and sarcoma pathogenesis and progression is emerging. Recent studies demonstrate that lncRNAs influence sarcoma cell proliferation, metastasis, and drug resistance. Additionally, lncRNA expression profiles are predictive of sarcoma prognosis. In this review, we summarize contemporary advances in the research of lncRNA biogenesis and functions in sarcoma. We also highlight the potential for lncRNAs to become innovative diagnostic and prognostic biomarkers as well as therapeutic targets in sarcoma. Full article
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Open AccessReview Function and Clinical Implications of Long Non-Coding RNAs in Melanoma
Int. J. Mol. Sci. 2017, 18(4), 715; https://doi.org/10.3390/ijms18040715
Received: 19 February 2017 / Revised: 16 March 2017 / Accepted: 17 March 2017 / Published: 28 March 2017
Cited by 5 | PDF Full-text (704 KB) | HTML Full-text | XML Full-text
Abstract
Metastatic melanoma is the most deadly type of skin cancer. Despite the success of immunotherapy and targeted agents, the majority of patients experience disease recurrence upon treatment and die due to their disease. Long non-coding RNAs (lncRNAs) are a new subclass of non-protein
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Metastatic melanoma is the most deadly type of skin cancer. Despite the success of immunotherapy and targeted agents, the majority of patients experience disease recurrence upon treatment and die due to their disease. Long non-coding RNAs (lncRNAs) are a new subclass of non-protein coding RNAs involved in (epigenetic) regulation of cell growth, invasion, and other important cellular functions. Consequently, recent research activities focused on the discovery of these lncRNAs in a broad spectrum of human diseases, especially cancer. Additional efforts have been undertaken to dissect the underlying molecular mechanisms employed by lncRNAs. In this review, we will summarize the growing evidence of deregulated lncRNA expression in melanoma, which is linked to tumor growth and progression. Moreover, we will highlight specific molecular pathways and modes of action for some well-studied lncRNAs and discuss their potential clinical implications. Full article
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Open AccessArticle Evaluation and Adaptation of a Laboratory-Based cDNA Library Preparation Protocol for Retrospective Sequencing of Archived MicroRNAs from up to 35-Year-Old Clinical FFPE Specimens
Int. J. Mol. Sci. 2017, 18(3), 627; https://doi.org/10.3390/ijms18030627
Received: 17 February 2017 / Revised: 2 March 2017 / Accepted: 8 March 2017 / Published: 14 March 2017
Cited by 1 | PDF Full-text (7800 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Formalin-fixed paraffin-embedded (FFPE) specimens, when used in conjunction with patient clinical data history, represent an invaluable resource for molecular studies of cancer. Even though nucleic acids extracted from archived FFPE tissues are degraded, their molecular analysis has become possible. In this study, we
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Formalin-fixed paraffin-embedded (FFPE) specimens, when used in conjunction with patient clinical data history, represent an invaluable resource for molecular studies of cancer. Even though nucleic acids extracted from archived FFPE tissues are degraded, their molecular analysis has become possible. In this study, we optimized a laboratory-based next-generation sequencing barcoded cDNA library preparation protocol for analysis of small RNAs recovered from archived FFPE tissues. Using matched fresh and FFPE specimens, we evaluated the robustness and reproducibility of our optimized approach, as well as its applicability to archived clinical specimens stored for up to 35 years. We then evaluated this cDNA library preparation protocol by performing a miRNA expression analysis of archived breast ductal carcinoma in situ (DCIS) specimens, selected for their relation to the risk of subsequent breast cancer development and obtained from six different institutions. Our analyses identified six miRNAs (miR-29a, miR-221, miR-375, miR-184, miR-363, miR-455-5p) differentially expressed between DCIS lesions from women who subsequently developed an invasive breast cancer (cases) and women who did not develop invasive breast cancer within the same time interval (control). Our thorough evaluation and application of this laboratory-based miRNA sequencing analysis indicates that the preparation of small RNA cDNA libraries can reliably be performed on older, archived, clinically-classified specimens. Full article
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Open AccessReview The Role and Molecular Mechanism of Non-Coding RNAs in Pathological Cardiac Remodeling
Int. J. Mol. Sci. 2017, 18(3), 608; https://doi.org/10.3390/ijms18030608
Received: 8 February 2017 / Revised: 5 March 2017 / Accepted: 7 March 2017 / Published: 10 March 2017
Cited by 5 | PDF Full-text (1112 KB) | HTML Full-text | XML Full-text
Abstract
Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. Studies show that ncRNAs are not only involved in cell proliferation, apoptosis, differentiation, metabolism and other physiological processes, but also involved in the pathogenesis of diseases. Cardiac remodeling is
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Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. Studies show that ncRNAs are not only involved in cell proliferation, apoptosis, differentiation, metabolism and other physiological processes, but also involved in the pathogenesis of diseases. Cardiac remodeling is the main pathological basis of a variety of cardiovascular diseases. Many studies have shown that the occurrence and development of cardiac remodeling are closely related with the regulation of ncRNAs. Recent research of ncRNAs in heart disease has achieved rapid development. Thus, we summarize here the latest research progress and mainly the molecular mechanism of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), in cardiac remodeling, aiming to look for new targets for heart disease treatment. Full article
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Open AccessReview Exosomes: From Garbage Bins to Promising Therapeutic Targets
Int. J. Mol. Sci. 2017, 18(3), 538; https://doi.org/10.3390/ijms18030538
Received: 14 December 2016 / Revised: 25 February 2017 / Accepted: 27 February 2017 / Published: 2 March 2017
Cited by 30 | PDF Full-text (3582 KB) | HTML Full-text | XML Full-text
Abstract
Intercellular communication via cell-released vesicles is a very important process for both normal and tumor cells. Cell communication may involve exosomes, small vesicles of endocytic origin that are released by all types of cells and are found in abundance in body fluids, including
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Intercellular communication via cell-released vesicles is a very important process for both normal and tumor cells. Cell communication may involve exosomes, small vesicles of endocytic origin that are released by all types of cells and are found in abundance in body fluids, including blood, saliva, urine, and breast milk. Exosomes have been shown to carry lipids, proteins, mRNAs, non-coding RNAs, and even DNA out of cells. They are more than simply molecular garbage bins, however, in that the molecules they carry can be taken up by other cells. Thus, exosomes transfer biological information to neighboring cells and through this cell-to-cell communication are involved not only in physiological functions such as cell-to-cell communication, but also in the pathogenesis of some diseases, including tumors and neurodegenerative conditions. Our increasing understanding of why cells release exosomes and their role in intercellular communication has revealed the very complex and sophisticated contribution of exosomes to health and disease. The aim of this review is to reveal the emerging roles of exosomes in normal and pathological conditions and describe the controversial biological role of exosomes, as it is now understood, in carcinogenesis. We also summarize what is known about exosome biogenesis, composition, functions, and pathways and discuss the potential clinical applications of exosomes, especially as biomarkers and novel therapeutic agents. Full article
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Open AccessReview Current Insights into Long Non-Coding RNAs (LncRNAs) in Prostate Cancer
Int. J. Mol. Sci. 2017, 18(2), 473; https://doi.org/10.3390/ijms18020473
Received: 16 January 2017 / Revised: 9 February 2017 / Accepted: 16 February 2017 / Published: 22 February 2017
Cited by 8 | PDF Full-text (496 KB) | HTML Full-text | XML Full-text
Abstract
The importance of long non-coding RNAs (lncRNAs) in the pathogenesis of various malignancies has been uncovered over the last few years. Their dysregulation often contributes to or is a result of tumour progression. In prostate cancer, the most common malignancy in men, lncRNAs
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The importance of long non-coding RNAs (lncRNAs) in the pathogenesis of various malignancies has been uncovered over the last few years. Their dysregulation often contributes to or is a result of tumour progression. In prostate cancer, the most common malignancy in men, lncRNAs can promote castration resistance, cell proliferation, invasion, and metastatic spread. Expression patterns of lncRNAs often change during tumour progression; their expression levels may constantly rise (e.g., HOX transcript antisense RNA, HOTAIR), or steadily decrease (e.g., downregulated RNA in cancer, DRAIC). In prostate cancer, lncRNAs likewise have diagnostic (e.g., prostate cancer antigen 3, PCA3), prognostic (e.g., second chromosome locus associated with prostate-1, SChLAP1), and predictive (e.g., metastasis-associated lung adenocarcinoma transcript-1, MALAT-1) functions. Considering their dynamic role in prostate cancer, lncRNAs may also serve as therapeutic targets, helping to prevent development of castration resistance, maintain stable disease, and prohibit metastatic spread. Full article
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Open AccessReview MicroRNAs: New Insight in Modulating Follicular Atresia: A Review
Int. J. Mol. Sci. 2017, 18(2), 333; https://doi.org/10.3390/ijms18020333
Received: 14 October 2016 / Revised: 13 January 2017 / Accepted: 23 January 2017 / Published: 9 February 2017
Cited by 3 | PDF Full-text (2032 KB) | HTML Full-text | XML Full-text
Abstract
Our understanding of the post-transcriptional mechanisms involved in follicular atresia is limited; however, an important development has been made in understanding the biological regulatory networks responsible for mediating follicular atresia. MicroRNAs have come to be seen as a key regulatory actor in determining
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Our understanding of the post-transcriptional mechanisms involved in follicular atresia is limited; however, an important development has been made in understanding the biological regulatory networks responsible for mediating follicular atresia. MicroRNAs have come to be seen as a key regulatory actor in determining cell fate in a wide range of tissues in normal and pathological processes. Profiling studies of miRNAs during follicular atresia and development have identified several putative miRNAs enriched in apoptosis signaling pathways. Subsequent in vitro and/or in vivo studies of granulosa cells have elucidated the functional role of some miRNAs along with their molecular pathways. In particular, the regulatory roles of some miRNAs have been consistently observed during studies of follicular cellular apoptosis. Continued work should gradually lead to better understanding of the role of miRNAs in this field. Ultimately, we expect this understanding will have substantial benefits for fertility management at both the in vivo or/and in vitro levels. The stable nature of miRNA holds remarkable promise in clinical use as a diagnostic tool and in reproductive medicine to solve the ever-increasing fertility problem. In this review, we summarize current knowledge of the involvement of miRNAs in follicular atresia, discuss the challenges for further work and pinpoint areas for future research. Full article
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Open AccessArticle The Long Non-Coding RNA RHPN1-AS1 Promotes Uveal Melanoma Progression
Int. J. Mol. Sci. 2017, 18(1), 226; https://doi.org/10.3390/ijms18010226
Received: 30 December 2016 / Revised: 14 January 2017 / Accepted: 16 January 2017 / Published: 23 January 2017
Cited by 3 | PDF Full-text (4051 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Increasing evidence suggests that aberrant long non-coding RNAs (lncRNAs) are significantly correlated with the pathogenesis, development and metastasis of cancers. RHPN1 antisense RNA 1 (RHPN1-AS1) is a 2030-bp transcript originating from human chromosome 8q24. However, the role of RHPN1-AS1 in uveal
[...] Read more.
Increasing evidence suggests that aberrant long non-coding RNAs (lncRNAs) are significantly correlated with the pathogenesis, development and metastasis of cancers. RHPN1 antisense RNA 1 (RHPN1-AS1) is a 2030-bp transcript originating from human chromosome 8q24. However, the role of RHPN1-AS1 in uveal melanoma (UM) remains to be clarified. In this study, we aimed to elucidate the molecular function of RHPN1-AS1 in UM. The RNA levels of RHPN1-AS1 in UM cell lines were examined using the quantitative real-time polymerase chain reaction (qRT-PCR). Short interfering RNAs (siRNAs) were designed to quench RHPN1-AS1 expression, and UM cells stably expressing short hairpin (sh) RHPN1-AS1 were established. Next, the cell proliferation and migration abilities were determined using a colony formation assay and a transwell migration/invasion assay. A tumor xenograft model in nude mice was established to confirm the function of RHPN1-AS1 in vivo. RHPN1-AS1 was significantly upregulated in a number of UM cell lines compared with the normal human retinal pigment epithelium (RPE) cell line. RHPN1-AS1 knockdown significantly inhibited UM cell proliferation and migration in vitro and in vivo. Our data suggest that RHPN1-AS1 could be an oncoRNA in UM, which may serve as a candidate prognostic biomarker and target for new therapies in malignant UM. Full article
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Open AccessArticle A Novel Combination RNAi toward Warburg Effect by Replacement with miR-145 and Silencing of PTBP1 Induces Apoptotic Cell Death in Bladder Cancer Cells
Int. J. Mol. Sci. 2017, 18(1), 179; https://doi.org/10.3390/ijms18010179
Received: 3 October 2016 / Revised: 27 December 2016 / Accepted: 10 January 2017 / Published: 17 January 2017
Cited by 5 | PDF Full-text (4280 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Bladder cancer is one of the most difficult malignancies to control. We explored the use of a novel RNA-interference method for a driver oncogene regulating cancer specific energy metabolism by the combination treatment with a small interfering RNA (siRNA) and a microRNA. After
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Bladder cancer is one of the most difficult malignancies to control. We explored the use of a novel RNA-interference method for a driver oncogene regulating cancer specific energy metabolism by the combination treatment with a small interfering RNA (siRNA) and a microRNA. After transfection of T24 and 253JB-V cells with miR-145 and/or siR-PTBP1, we examined the effects of cell growth and gene expression by performing the trypan blue dye exclusion test, Western blot, Hoechst 33342 staining, reverse transcription polymerase chain reaction (RT-PCR), and electron microscopy. The anti-cancer effects of xenograft model mice with miR-145 and/or siR-PTBP1 were then assessed. The combination treatment induced the deeper and longer growth inhibition and reduced the levels of both mRNA and protein expression of c-Myc and polypyrimidine tract-binding protein 1 (PTBP1) more than each single treatment. Notably, the combination treatment not only impaired the cancer specific energy metabolism by inhibiting c-Myc/PTBP1/PKMs axis but also inactivated MAPK/ERK and PI3K/AKT pathways examined in vitro and in vivo. Furthermore, the combination treatment induced apoptosis or autophagy; but, in some cells, apoptotic cell death was accompanied by autophagy, because the condensation of chromatin and many autophagosomes were coexistent. This combination treatment could be a novel RNA-interference strategy through the systemic silencing of the Warburg effect-promoting driver oncogene PTBP1 in bladder cancer cells. Full article
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Open AccessArticle Role of miR-34a-5p in Hematopoietic Progenitor Cells Proliferation and Fate Decision: Novel Insights into the Pathogenesis of Primary Myelofibrosis
Int. J. Mol. Sci. 2017, 18(1), 145; https://doi.org/10.3390/ijms18010145
Received: 28 October 2016 / Revised: 5 January 2017 / Accepted: 6 January 2017 / Published: 13 January 2017
PDF Full-text (9138 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Primary Myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by a skewed megakaryopoiesis and an overproduction of proinflammatory and profibrotic mediators that lead to the development of bone marrow (BM) fibrosis. Since we recently uncovered the upregulation of miR-34a-5p in PMF CD34+
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Primary Myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by a skewed megakaryopoiesis and an overproduction of proinflammatory and profibrotic mediators that lead to the development of bone marrow (BM) fibrosis. Since we recently uncovered the upregulation of miR-34a-5p in PMF CD34+ hematopoietic progenitor cells (HPCs), in order to elucidate its role in PMF pathogenesis here we unravelled the effects of miR-34a-5p overexpression in HPCs. We showed that enforced expression of miR-34a-5p partially constrains proliferation and favours the megakaryocyte and monocyte/macrophage commitment of HPCs. Interestingly, we identified lymphoid enhancer-binding factor 1 (LEF1) and nuclear receptor subfamily 4, group A, member 2 (NR4A2) transcripts as miR-34a-5p-targets downregulated after miR-34a-5p overexpression in HPCs as well as in PMF CD34+ cells. Remarkably, the knockdown of NR4A2 in HPCs mimicked the antiproliferative effects of miR-34a-5p overexpression, while the silencing of LEF1 phenocopied the effects of miR-34a-5p overexpression on HPCs lineage choice, by favouring the megakaryocyte and monocyte/macrophage commitment. Collectively our data unravel the role of miR-34a-5p in HPCs fate decision and suggest that the increased expression of miR-34a-5p in PMF HPCs could be important for the skewing of megakaryopoiesis and the production of monocytes, that are key players in BM fibrosis in PMF patients. Full article
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Open AccessReview Therapeutic Resistance in Acute Myeloid Leukemia: The Role of Non-Coding RNAs
Int. J. Mol. Sci. 2016, 17(12), 2080; https://doi.org/10.3390/ijms17122080
Received: 4 November 2016 / Revised: 1 December 2016 / Accepted: 5 December 2016 / Published: 10 December 2016
Cited by 11 | PDF Full-text (676 KB) | HTML Full-text | XML Full-text
Abstract
Acute myeloid leukemia (AML) is caused by malignant transformation of hematopoietic stem or progenitor cells and displays the most frequent acute leukemia in adults. Although some patients can be cured with high dose chemotherapy and allogeneic hematopoietic stem cell transplantation, the majority still
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Acute myeloid leukemia (AML) is caused by malignant transformation of hematopoietic stem or progenitor cells and displays the most frequent acute leukemia in adults. Although some patients can be cured with high dose chemotherapy and allogeneic hematopoietic stem cell transplantation, the majority still succumbs to chemoresistant disease. Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNA fragments and act as key players in the regulation of both physiologic and pathologic gene expression profiles. Aberrant expression of various non-coding RNAs proved to be of seminal importance in the pathogenesis of AML, as well in the development of resistance to chemotherapy. In this review, we discuss the role of miRNAs and lncRNAs with respect to sensitivity and resistance to treatment regimens currently used in AML and provide an outlook on potential therapeutic targets emerging thereof. Full article
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Open AccessArticle Relevance of MicroRNA200 Family and MicroRNA205 for Epithelial to Mesenchymal Transition and Clinical Outcome in Biliary Tract Cancer Patients
Int. J. Mol. Sci. 2016, 17(12), 2053; https://doi.org/10.3390/ijms17122053
Received: 3 November 2016 / Revised: 30 November 2016 / Accepted: 1 December 2016 / Published: 7 December 2016
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Abstract
Extensive stromal interaction is one reason for the dismal outcome of biliary tract cancer (BTC) patients. Epithelial to mesenchymal transition (EMT) is involved in tumor invasion and metastasis and is partly regulated by microRNAs (miRs). This study explores the expression of anti-EMT miR200
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Extensive stromal interaction is one reason for the dismal outcome of biliary tract cancer (BTC) patients. Epithelial to mesenchymal transition (EMT) is involved in tumor invasion and metastasis and is partly regulated by microRNAs (miRs). This study explores the expression of anti-EMT miR200 family (miR141, −200a/b/c, −429) and miR205 as well as the EMT-related proteins E-cadherin and vimentin in a panel of BTC cell lines and clinical specimens by quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry, respectively. MicroRNA expression was correlated to (i) the expression patterns of E-cadherin and vimentin; (ii) clinicopathological characteristics; and (iii) survival data. MicroRNA-200 family and miR205 were expressed in all BTC cells and clinical specimens. E-cadherin and vimentin showed a mutually exclusive expression pattern in both, in vitro and in vivo. Expression of miR200 family members positively correlated with E-cadherin and negatively with vimentin expression in BTC cells and specimens. High expression of miR200 family members (but not miR205) and E-cadherin was associated with longer survival, while low miR200 family and high vimentin expression was a predictor of unfavorable survival. Overall, the current study demonstrates the relevance of the miR200 family in EMT of BTC tumors and suggests these miRs as predictors for positive outcome. Full article
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Open AccessArticle Screening the Expression Changes in MicroRNAs and Their Target Genes in Mature Cementoblasts Stimulated with Cyclic Tensile Stress
Int. J. Mol. Sci. 2016, 17(12), 2024; https://doi.org/10.3390/ijms17122024
Received: 11 October 2016 / Revised: 22 November 2016 / Accepted: 24 November 2016 / Published: 7 December 2016
Cited by 3 | PDF Full-text (2970 KB) | HTML Full-text | XML Full-text
Abstract
Cementum is a thin layer of cementoblast-produced mineralized tissue covering the root surfaces of teeth. Mechanical forces, which are produced during masticatory activity, play a paramount role in stimulating cementoblastogenesis, which thereby facilitates the maintenance, remodeling and integrity of cementum. However, hitherto, the
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Cementum is a thin layer of cementoblast-produced mineralized tissue covering the root surfaces of teeth. Mechanical forces, which are produced during masticatory activity, play a paramount role in stimulating cementoblastogenesis, which thereby facilitates the maintenance, remodeling and integrity of cementum. However, hitherto, the extent to which a post-transcriptional modulation mechanism is involved in this process has rarely been reported. In this study, a mature murine cementoblast cell line OCCM-30 cells (immortalized osteocalcin positive cementoblasts) was cultured and subjected to cyclic tensile stress (0.5 Hz, 2000 µstrain). We showed that the cyclic tensile stress could not only rearrange the cell alignment, but also influence the proliferation in an S-shaped manner. Furthermore, cyclic tensile stress could significantly promote cementoblastogenesis-related genes, proteins and mineralized nodules. From the miRNA array analyses, we found that 60 and 103 miRNAs were significantly altered 6 and 18 h after the stimulation using cyclic tensile stress, respectively. Based on a literature review and bioinformatics analyses, we found that miR-146b-5p and its target gene Smad4 play an important role in this procedure. The upregulation of miR-146b-5p and downregulation of Smad4 induced by the tensile stress were further confirmed by qRT-PCR. The direct binding of miR-146b-5p to the three prime untranslated region (3′ UTR) of Smad4 was established using a dual-luciferase reporter assay. Taken together, these results suggest an important involvement of miR-146b-5p and its target gene Smad4 in the cementoblastogenesis of mature cementoblasts. Full article
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Open AccessArticle Comprehensive Analysis of miRNome Alterations in Response to Sorafenib Treatment in Colorectal Cancer Cells
Int. J. Mol. Sci. 2016, 17(12), 2011; https://doi.org/10.3390/ijms17122011
Received: 25 August 2016 / Revised: 18 November 2016 / Accepted: 24 November 2016 / Published: 1 December 2016
Cited by 7 | PDF Full-text (4359 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs (miRNAs) are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer (CRC). Sorafenib, a multi-kinase inhibitor which has been approved for the treatment of liver, renal and thyroid cancer,
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MicroRNAs (miRNAs) are master regulators of drug resistance and have been previously proposed as potential biomarkers for the prediction of therapeutic response in colorectal cancer (CRC). Sorafenib, a multi-kinase inhibitor which has been approved for the treatment of liver, renal and thyroid cancer, is currently being studied as a monotherapy in selected molecular subtypes or in combination with other drugs in metastatic CRC. In this study, we explored sorafenib-induced cellular effects in Kirsten rat sarcoma viral oncogene homolog olog (KRAS) wild-type and KRAS-mutated CRC cell lines (Caco-2 and HRT-18), and finally profiled expression changes of specific miRNAs within the miRNome (>1000 human miRNAs) after exposure to sorafenib. Overall, sorafenib induced a time- and dose-dependent growth-inhibitory effect through S-phase cell cycle arrest in KRAS wild-type and KRAS-mutated CRC cells. In HRT-18 cells, two human miRNAs (hsa-miR-597 and hsa-miR-720) and two small RNAs (SNORD 13 and hsa-miR-3182) were identified as specifically sorafenib-induced. In Caco-2 cells, nine human miRNAs (hsa-miR-3142, hsa-miR-20a, hsa-miR-4301, hsa-miR-1290, hsa-miR-4286, hsa-miR-3182, hsa-miR-3142, hsa-miR-1246 and hsa-miR-720) were identified to be differentially regulated post sorafenib treatment. In conclusion, we confirmed sorafenib as a potential anti-neoplastic treatment strategy for CRC cells by demonstrating a growth-inhibitory and cell cycle–arresting effect of this drug. Changes in the miRNome indicate that some specific miRNAs might be relevant as indicators for sorafenib response, drug resistance and potential targets for combinatorial miRNA-based drug strategies. Full article
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Open AccessReview Roles of MicroRNA across Prenatal and Postnatal Periods
Int. J. Mol. Sci. 2016, 17(12), 1994; https://doi.org/10.3390/ijms17121994
Received: 16 October 2016 / Revised: 11 November 2016 / Accepted: 17 November 2016 / Published: 28 November 2016
Cited by 5 | PDF Full-text (824 KB) | HTML Full-text | XML Full-text
Abstract
Communication between mother and offspring in mammals starts at implantation via the maternal–placental–fetal axis, and continues postpartum via milk targeted to the intestinal mucosa. MicroRNAs (miRNAs), short, noncoding single-stranded RNAs, of about 22 nucleotides in length, are actively involved in many developmental and
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Communication between mother and offspring in mammals starts at implantation via the maternal–placental–fetal axis, and continues postpartum via milk targeted to the intestinal mucosa. MicroRNAs (miRNAs), short, noncoding single-stranded RNAs, of about 22 nucleotides in length, are actively involved in many developmental and physiological processes. Here we highlight the role of miRNA in the dynamic signaling that guides infant development, starting from implantation of conceptus and persisting through the prenatal and postnatal periods. miRNAs in body fluids, particularly in amniotic fluid, umbilical cord blood, and breast milk may offer new opportunities to investigate physiological and/or pathological molecular mechanisms that portend to open novel research avenues for the identification of noninvasive biomarkers. Full article
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Open AccessArticle Microarray Expression Profiling of Long Non-Coding RNAs Involved in Nasopharyngeal Carcinoma Metastasis
Int. J. Mol. Sci. 2016, 17(11), 1956; https://doi.org/10.3390/ijms17111956
Received: 20 October 2016 / Revised: 15 November 2016 / Accepted: 15 November 2016 / Published: 23 November 2016
Cited by 5 | PDF Full-text (3397 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Increasing evidence has demonstrated a significant role for long non-coding RNAs (lncRNAs) in tumorigenesis. However, their functions in nasopharyngeal carcinoma (NPC) metastasis remain largely unknown. In this study, a model comparing high and low metastatic NPC cell lines (5-8F vs. 6-10B and S18
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Increasing evidence has demonstrated a significant role for long non-coding RNAs (lncRNAs) in tumorigenesis. However, their functions in nasopharyngeal carcinoma (NPC) metastasis remain largely unknown. In this study, a model comparing high and low metastatic NPC cell lines (5-8F vs. 6-10B and S18 vs. S26) was constructed to determine the expression profile of lncRNAs using the microarray analysis, and we found 167 lncRNAs and 209 mRNAs were differentially expressed. Bioinformatic analysis indicated that the dysregulated mRNAs participated in important biological regulatory functions in NPC. Validation of 26 significantly dysregulated lncRNAs by qRT-PCR showed the expression patterns of 22 lncRNAs were in accordance with the microarray data. Furthermore, the expression level of ENST00000470135, which was the most upregulated lncRNA in high metastatic cell lines, was significantly higher in NPC cell lines and tissues with lymph node metastasis (LNM) and knocking down ENST00000470135 suppressed the migration, invasion and proliferation of NPC cells in vitro. In conclusion, our study revealed expression patterns of lncRNAs in NPC metastasis. The dysregulated lncRNAs may act as novel biomarkers and therapeutic targets for NPC. Full article
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Open AccessArticle MicroRNAs 10a and 10b Regulate the Expression of Human Platelet Glycoprotein Ibα for Normal Megakaryopoiesis
Int. J. Mol. Sci. 2016, 17(11), 1873; https://doi.org/10.3390/ijms17111873
Received: 17 August 2016 / Revised: 3 October 2016 / Accepted: 3 November 2016 / Published: 9 November 2016
Cited by 2 | PDF Full-text (1303 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs are a class of small non-coding RNAs that bind to the three prime untranslated region (3′-UTR) of target mRNAs. They cause a cleavage or an inhibition of the translation of target mRNAs, thus regulating gene expression. Here, we employed three prediction tools
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MicroRNAs are a class of small non-coding RNAs that bind to the three prime untranslated region (3′-UTR) of target mRNAs. They cause a cleavage or an inhibition of the translation of target mRNAs, thus regulating gene expression. Here, we employed three prediction tools to search for potential miRNA target sites in the 3′-UTR of the human platelet glycoprotein (GP) 1BA gene. A luciferase reporter assay shows that miR-10a and -10b sites are functional. When miR-10a or -10b mimics were transfected into the GP Ibβ/GP IX-expressing cells, along with a DNA construct harboring both the coding and 3′-UTR sequences of the human GP1BA gene, we found that they inhibit the transient expression of GP Ibα on the cell surface. When the miR-10a or -10b mimics were introduced into murine progenitor cells, upon megakaryocyte differentiation, we found that GP Ibα mRNA expression was markedly reduced, suggesting that a miRNA-induced mRNA degradation is at work. Thus, our study identifies GP Ibα as a novel target of miR-10a and -10b, suggesting that a drastic reduction in the levels of miR-10a and -10b in the late stage of megakaryopoiesis is required to allow the expression of human GP Ibα and the formation of the GP Ib-IX-V complex. Full article
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Open AccessArticle X-Linked miRNAs Associated with Gender Differences in Rheumatoid Arthritis
Int. J. Mol. Sci. 2016, 17(11), 1852; https://doi.org/10.3390/ijms17111852
Received: 22 August 2016 / Revised: 17 October 2016 / Accepted: 31 October 2016 / Published: 8 November 2016
Cited by 9 | PDF Full-text (2912 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease that predominantly affects women. MicroRNAs have emerged as crucial regulators of the immune system, whose expression is deregulated in RA. We aimed at quantifying the expression level of 14 miRNAs located on the X chromosome and
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Rheumatoid arthritis (RA) is an autoimmune disease that predominantly affects women. MicroRNAs have emerged as crucial regulators of the immune system, whose expression is deregulated in RA. We aimed at quantifying the expression level of 14 miRNAs located on the X chromosome and at identifying whether differences are associated with disease and/or sex. A case–control study of 21 RA patients and 22 age- and sex-matched healthy controls was performed on peripheral blood mononuclear cells. The expression level of five miRNAs (miR-221, miR-222, miR-532, miR-106a, and miR-98) was significantly different between RA and controls when stratifying by sex, and the expression level of four miRNAs (miR-222, miR-532, miR-98, and miR-92a) was significantly different between RA females and males. The expression quantitative trait loci (eQTL) analysis revealed a significant gender effect of the FoxP3 promoter polymorphism rs3761548A/C on miR-221, miR-222 and miR-532 expression levels, and of the FoxP3 polymorphism rs2232365A/G on miR-221 expression levels in PBMC of RA patients. These data further support the involvement of the X chromosome in RA susceptibility. X-linked miRNAs, in the context of sex differences, might provide novel insight into new molecular mechanisms and potential therapeutic targets in RA for disease treatment and prevention. Full article
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Open AccessArticle Upregulated MicroRNA-25 Mediates the Migration of Melanoma Cells by Targeting DKK3 through the WNT/β-Catenin Pathway
Int. J. Mol. Sci. 2016, 17(11), 1124; https://doi.org/10.3390/ijms17111124
Received: 14 April 2016 / Revised: 20 May 2016 / Accepted: 31 May 2016 / Published: 27 October 2016
Cited by 7 | PDF Full-text (4800 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Previous research indicates that microRNA-25 (miR-25) regulates carcinogenesis and the progression of various cancers, but the role of miR-25 in melanoma remains unclear. We observed that miR-25 was significantly upregulated in melanoma cell lines and tissue samples. Downregulation of miR-25 markedly suppressed invasion
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Previous research indicates that microRNA-25 (miR-25) regulates carcinogenesis and the progression of various cancers, but the role of miR-25 in melanoma remains unclear. We observed that miR-25 was significantly upregulated in melanoma cell lines and tissue samples. Downregulation of miR-25 markedly suppressed invasion and proliferation of melanoma cells in vitro; however, overexpression of miR-25 markedly increased melanoma cell invasion and proliferation. Moreover, we observed Dickkopf-related protein 3 (DKK3) as a direct target of miR-25 in vitro. Upregulation of DKK3 partially attenuated the oncogenic effect of miR-25 on melanoma cells. Ectopic expression of miR-25 in melanoma cells induced β-catenin accumulation in nuclear and inhibited TCF4 (T cell factor 4) activity, as well as the expression of c-Myc and Cyclin D1. In a nude xenograft model, miR-25 upregulation significantly increased A375 melanoma growth. In summary, miR-25 is upregulated in melanoma and promotes melanoma cell proliferation and invasion, partially by targeting DKK3. These results were indicated that miR-25 may serve as a potential target for the treatment of melanoma in the future. Full article
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Open AccessReview miR-155: A Novel Target in Allergic Asthma
Int. J. Mol. Sci. 2016, 17(10), 1773; https://doi.org/10.3390/ijms17101773
Received: 14 August 2016 / Revised: 19 October 2016 / Accepted: 20 October 2016 / Published: 24 October 2016
Cited by 7 | PDF Full-text (662 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
MicroRNAs (miRNAs), a class of small non-coding RNAs of 18–24 nucleotides in length, function to posttranscriptionally regulate protein expression. miR-155 was one of the first identified and, to date, the most studied miRNA, and has been linked to various cellular processes such as
[...] Read more.
MicroRNAs (miRNAs), a class of small non-coding RNAs of 18–24 nucleotides in length, function to posttranscriptionally regulate protein expression. miR-155 was one of the first identified and, to date, the most studied miRNA, and has been linked to various cellular processes such as modulation of immune responses and oncogenesis. Previous studies have identified miR-155 as a crucial positive regulator of Th1 immune response in autoimmune diseases, but as a suppressor of Th2 immunity in allergic disorders. However, recent studies have found new evidence that miR-155 plays an indispensible role in allergic asthma. This review summarizes the recent findings with respect to miR-155 in immune responses and the underlying mechanisms responsible for miR-155-related allergic diseases, as well as the similarities between miR-155 and glucocorticoids in immunity. Full article
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Open AccessArticle A Comprehensive MicroRNA Expression Profile of Liver and Lung Metastases of Colorectal Cancer with Their Corresponding Host Tissue and Its Prognostic Impact on Survival
Int. J. Mol. Sci. 2016, 17(10), 1755; https://doi.org/10.3390/ijms17101755
Received: 20 July 2016 / Revised: 4 October 2016 / Accepted: 12 October 2016 / Published: 21 October 2016
Cited by 3 | PDF Full-text (1486 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
MicroRNAs are small non-coding RNAs with a length of 18–25 nucleotides. They can regulate tumor invasion and metastasis by changing the expression and translation of their target mRNAs. Their expression is substantially altered in colorectal cancer cells as well as in the adjacent
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MicroRNAs are small non-coding RNAs with a length of 18–25 nucleotides. They can regulate tumor invasion and metastasis by changing the expression and translation of their target mRNAs. Their expression is substantially altered in colorectal cancer cells as well as in the adjacent tumor-associated stroma. Both of these compartments have a mutual influence on tumor progression. In the development of metastases, cancer cells initially interact with the host tissue. Therefore, compartment-specific expression signatures of these three locations—tumor, associated stroma, and host tissue—can provide new insights into the complex tumor biology of colorectal cancer. Frozen tissue samples of colorectal liver (n = 25) and lung metastases (n = 24) were laser microdissected to separate tumor cells and the adjacent tumor-associated stroma cells. Additionally, normal lung and liver tissue was collected from the same patients. We performed a microarray analysis in four randomly selected liver metastases and four randomly selected lung metastases, analyzing a total of 939 human miRNAs. miRNAs with a significant change >2-fold between the tumor, tumor stroma, and host tissue were analyzed in all samples using RT-qPCR (11 miRNAs) and correlated with the clinical data. We found a differential expression of several miRNAs between the tumor, the tumor-associated stroma, and the host tissue compartment. When comparing liver and lung metastases, miR-194 showed a 1.5-fold; miR-125, miR-127, and miR-192 showed a 2.5-fold; miR-19 and miR-215 a 3-fold; miR-145, miR-199-3, and miR-429 a 5-fold; miR-21 a 7-fold; and, finally, miR-199-5 a 12.5-fold downregulation in liver metastases compared to lung metastases. Furthermore miR-19, miR-125, miR-127, miR-192, miR-194, miR-199-5, and miR-215 showed a significant upregulation in the normal liver tissue compared to the normal lung tissue. Univariate analysis identified an association of poor survival with the expression of miR-125 (p = 0.05), miR-127 (p = 0.001), miR-145 (p = 0.005), miR-192 (p = 0.015), miR-194 (0.003), miR-199-5 (p = 0.008), miR-215 (p < 0.001), and miR-429 (p = 0.03) in the host liver tissue of the liver metastases. Colorectal liver and lung metastases have a unique miRNA expression profile. miRNA expression in the host tissue of colorectal liver metastases seems to be able to influence tumor progression and survival. These findings can be used in the development of tailored therapies. Full article
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Open AccessReview Regulatory Roles of MicroRNAs in Diabetes
Int. J. Mol. Sci. 2016, 17(10), 1729; https://doi.org/10.3390/ijms17101729
Received: 17 August 2016 / Revised: 2 October 2016 / Accepted: 9 October 2016 / Published: 17 October 2016
Cited by 10 | PDF Full-text (602 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs in eukaryotes, have been recognized as significant regulators of gene expression through post-transcriptional mechanisms. To date, >2000 miRNAs have been identified in the human genome, and they orchestrate a variety of biological and pathological
[...] Read more.
MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs in eukaryotes, have been recognized as significant regulators of gene expression through post-transcriptional mechanisms. To date, >2000 miRNAs have been identified in the human genome, and they orchestrate a variety of biological and pathological processes. Disruption of miRNA levels correlates with many diseases, including diabetes mellitus, a complex multifactorial metabolic disorder affecting >400 million people worldwide. miRNAs are involved in the pathogenesis of diabetes mellitus by affecting pancreatic β-cell functions, insulin resistance, or both. In this review, we summarize the investigations of the regulatory roles of important miRNAs in diabetes, as well as the potential of circulating miRNAs as diagnostic markers for diabetes mellitus. Full article
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Open AccessArticle MicroRNA-375 Functions as a Tumor-Suppressor Gene in Gastric Cancer by Targeting Recepteur d’Origine Nantais
Int. J. Mol. Sci. 2016, 17(10), 1633; https://doi.org/10.3390/ijms17101633
Received: 26 July 2016 / Revised: 1 September 2016 / Accepted: 12 September 2016 / Published: 27 September 2016
Cited by 7 | PDF Full-text (10930 KB) | HTML Full-text | XML Full-text
Abstract
Emerging evidence supports a fundamental role for microRNAs (miRNA) in regulating cancer metastasis. Recently, microRNA-375 (miR-375) was reported to be downregulated in many types of cancers, including gastric cancer. Increase in the expression of Recepteur d’Origine Nantais (RON), a receptor tyrosine
[...] Read more.
Emerging evidence supports a fundamental role for microRNAs (miRNA) in regulating cancer metastasis. Recently, microRNA-375 (miR-375) was reported to be downregulated in many types of cancers, including gastric cancer. Increase in the expression of Recepteur d’Origine Nantais (RON), a receptor tyrosine kinase, has been reported in tumors. However, the function of miR-375 and RON expression in gastric cancer metastasis has not been sufficiently studied. In silico analysis identified miR-375 binding sites in the 3′-untranslated regions (3′-UTR) of the RON-encoding gene. Expression of miR-375 resulted in reduced activity of a luciferase reporter containing the 3′-UTR fragments of RON-encoding mRNA, confirming that miR-375 directly targets the 3′-UTR of RON mRNA. Moreover, we found that overexpression of miR-375 inhibited mRNA and protein expression of RON, which was accompanied by the suppression of cell proliferation, migration, and invasion in gastric cancer AGS and MKN-28 cells. Ectopic miR-375 expression also induced G1 cell cycle arrest through a decrease in the expression of cyclin D1, cyclin D3, and in the phosphorylation of retinoblastoma (Rb). Knockdown of RON by RNAi, similar to miR-375 overexpression, suppressed tumorigenic properties and induced G1 arrest through a decrease in the expression of cyclin D1, cyclin D3, and in the phosphorylation of Rb. Thus, our study provides evidence that miR-375 acts as a suppressor of metastasis in gastric cancer by targeting RON, and might represent a new potential therapeutic target for gastric cancer. Full article
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Open AccessArticle miR33a/miR33b* and miR122 as Possible Contributors to Hepatic Lipid Metabolism in Obese Women with Nonalcoholic Fatty Liver Disease
Int. J. Mol. Sci. 2016, 17(10), 1620; https://doi.org/10.3390/ijms17101620
Received: 3 August 2016 / Revised: 13 September 2016 / Accepted: 13 September 2016 / Published: 24 September 2016
Cited by 3 | PDF Full-text (1245 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Specific miRNA expression profiles have been shown to be associated with nonalcoholic fatty liver disease (NAFLD). We examined the correlation between the circulating levels and hepatic expression of miR122 and miR33a/b*, the key lipid metabolism-related gene expression and the clinicopathological factors of obese
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Specific miRNA expression profiles have been shown to be associated with nonalcoholic fatty liver disease (NAFLD). We examined the correlation between the circulating levels and hepatic expression of miR122 and miR33a/b*, the key lipid metabolism-related gene expression and the clinicopathological factors of obese women with NAFLD. We measured miR122 and miR33a/b* expression in liver samples from 62 morbidly obese (MO), 30 moderately obese (ModO), and eight normal-weight controls. MiR122 and miR33a/b* expression was analyzed by qRT-PCR. Additionally, miR122 and miR33b* circulating levels were analyzed in 122 women. Hepatic miR33b* expression was increased in MO compared to ModO and controls, whereas miR122 expression was decreased in the MO group compared to ModO. In obese cohorts, miR33b* expression was increased in nonalcoholic steatohepatitis (NASH). Regarding circulating levels, MO patients with NASH showed higher miR122 levels than MO with simple steatosis (SS). These circulating levels are good predictors of histological features associated with disease severity. MO is associated with altered hepatic miRNA expression. In obese women, higher miR33b* liver expression is associated with NASH. Moreover, multiple correlations between miRNAs and the expression of genes related to lipid metabolism were found, that would suggest a miRNA-host gene circuit. Finally, miR122 circulating levels could be included in a panel of different biomarkers to improve accuracy in the non-invasive diagnosis of NASH. Full article
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Open AccessArticle Long Noncoding RNA lncCAMTA1 Promotes Proliferation and Cancer Stem Cell-Like Properties of Liver Cancer by Inhibiting CAMTA1
Int. J. Mol. Sci. 2016, 17(10), 1617; https://doi.org/10.3390/ijms17101617
Received: 7 July 2016 / Revised: 3 September 2016 / Accepted: 5 September 2016 / Published: 23 September 2016
Cited by 11 | PDF Full-text (4057 KB) | HTML Full-text | XML Full-text | Supplementary Files
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Hepatocellular carcinoma (HCC) is the most common subtype of liver malignancy, and it is characterized by poor prognosis because of cancer stem cell (CSC)-mediated high postsurgical recurrence rates. Thus, targeting CSCs, or HCC cells with CSC-like properties, is an effective strategy for HCC
[...] Read more.
Hepatocellular carcinoma (HCC) is the most common subtype of liver malignancy, and it is characterized by poor prognosis because of cancer stem cell (CSC)-mediated high postsurgical recurrence rates. Thus, targeting CSCs, or HCC cells with CSC-like properties, is an effective strategy for HCC therapy. Here, using long noncoding RNA (lncRNA) microarray analysis, we identified a novel lncRNA termed lncCAMTA1 that is increased in both liver CSCs and HCC. High lncCAMTA1 expression in HCC indicates poor clinical outcome. In vitro and in vivo functional experiments showed that overexpression of lncCAMTA1 promotes HCC cell proliferation, CSC-like properties, and tumorigenesis. Conversely, depletion of lncCAMTA1 inhibits HCC cell proliferation, CSC-like properties, and tumorigenesis. Mechanistically, we demonstrated that lncCAMTA1 physically associates with the calmodulin binding transcription activator 1 (CAMTA1) promoter, induces a repressive chromatin structure, and inhibits CAMTA1 transcription. Furthermore, CAMTA1 is required for the effects of lncCAMTA1 on HCC cell proliferation and CSC-like properties, and the expression of lncCAMTA1 and CAMTA1 is significantly negatively correlated in HCC tissues. Collectively, our study revealed the important roles and underlying molecular mechanisms of lncCAMTA1 on HCC, and suggested that lncCAMTA1 could be an effective prognostic factor and a potential therapeutic target for HCC. Full article
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Open AccessCommentary A MicroRNA that Regulates TLR-Mediated Fibrosis
Int. J. Mol. Sci. 2016, 17(9), 1519; https://doi.org/10.3390/ijms17091519
Received: 3 August 2016 / Revised: 7 September 2016 / Accepted: 7 September 2016 / Published: 9 September 2016
Cited by 1 | PDF Full-text (146 KB) | HTML Full-text | XML Full-text
Abstract
Hepatic damage can be caused by an array of factors which, if sustained, can lead to hepatic fibrosis.[...] Full article
Open AccessReview Current Status of Long Non-Coding RNAs in Human Breast Cancer
Int. J. Mol. Sci. 2016, 17(9), 1485; https://doi.org/10.3390/ijms17091485
Received: 27 July 2016 / Revised: 22 August 2016 / Accepted: 26 August 2016 / Published: 6 September 2016
Cited by 15 | PDF Full-text (275 KB) | HTML Full-text | XML Full-text
Abstract
Breast cancer represents a major health burden in Europe and North America, as recently published data report breast cancer as the second leading cause of cancer related death in women worldwide. Breast cancer is regarded as a highly heterogeneous disease in terms of
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Breast cancer represents a major health burden in Europe and North America, as recently published data report breast cancer as the second leading cause of cancer related death in women worldwide. Breast cancer is regarded as a highly heterogeneous disease in terms of clinical course and biological behavior and can be divided into several molecular subtypes, with different prognosis and treatment responses. The discovery of numerous non-coding RNAs has dramatically changed our understanding of cell biology, especially the pathophysiology of cancer. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts >200 nucleotides in length. Several studies have demonstrated their role as key regulators of gene expression, cell biology and carcinogenesis. Deregulated expression levels of lncRNAs have been observed in various types of cancers including breast cancer. lncRNAs are involved in cancer initiation, progression, and metastases. In this review, we summarize the recent literature to highlight the current status of this class of long non-coding lncRNAs in breast cancer. Full article
Open AccessArticle MicroRNA-378 Alleviates Cerebral Ischemic Injury by Negatively Regulating Apoptosis Executioner Caspase-3
Int. J. Mol. Sci. 2016, 17(9), 1427; https://doi.org/10.3390/ijms17091427
Received: 22 July 2016 / Revised: 14 August 2016 / Accepted: 19 August 2016 / Published: 2 September 2016
Cited by 6 | PDF Full-text (8154 KB) | HTML Full-text | XML Full-text
Abstract
miRNAs have been linked to many human diseases, including ischemic stroke, and are being pursued as clinical diagnostics and therapeutic targets. Among the aberrantly expressed miRNAs in our previous report using large-scale microarray screening, the downregulation of miR-378 in the peri-infarct region of
[...] Read more.
miRNAs have been linked to many human diseases, including ischemic stroke, and are being pursued as clinical diagnostics and therapeutic targets. Among the aberrantly expressed miRNAs in our previous report using large-scale microarray screening, the downregulation of miR-378 in the peri-infarct region of middle cerebral artery occluded (MCAO) mice can be reversed by hypoxic preconditioning (HPC). In this study, the role of miR-378 in the ischemic injury was further explored. We found that miR-378 levels significantly decreased in N2A cells following oxygen-glucose deprivation (OGD) treatment. Overexpression of miR-378 significantly enhanced cell viability, decreased TUNEL-positive cells and the immunoreactivity of cleaved-caspase-3. Conversely, downregulation of miR-378 aggravated OGD-induced apoptosis and ischemic injury. By using bioinformatic algorithms, we discovered that miR-378 may directly bind to the predicted 3′-untranslated region (UTR) of Caspase-3 gene. The protein level of caspase-3 increased significantly upon OGD treatment, and can be downregulated by pri-miR-378 transfection. The luciferase reporter assay confirmed the binding of miR-378 to the 3′-UTR of Caspase-3 mRNA and repressed its translation. In addition, miR-378 agomir decreased cleaved-caspase-3 ratio, reduced infarct volume and neural cell death induced by MCAO. Furthermore, caspase-3 knockdown could reverse anti-miR-378 mediated neuronal injury. Taken together, our data demonstrated that miR-378 attenuated ischemic injury by negatively regulating the apoptosis executioner, caspase-3, providing a potential therapeutic target for ischemic stroke. Full article
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Open AccessArticle A Long Noncoding RNA ZEB1-AS1 Promotes Tumorigenesis and Predicts Poor Prognosis in Glioma
Int. J. Mol. Sci. 2016, 17(9), 1431; https://doi.org/10.3390/ijms17091431
Received: 7 July 2016 / Revised: 19 August 2016 / Accepted: 22 August 2016 / Published: 30 August 2016
Cited by 25 | PDF Full-text (6125 KB) | HTML Full-text | XML Full-text
Abstract
Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in
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Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in glioma tissues, being closely related to clinical stage of glioma. Moreover, patients with high ZEB1-AS1 levels had poor prognoses, with the evidence provided by multivariate Cox regression analysis indicating that ZEB1-AS1 expression could serve as an independent prognostic factor in glioma patients. Functionally, silencing of ZEB1-AS1 could significantly inhibit cell proliferation, migration, and invasion, as well as promote apoptosis. Knockdown of ZEB1-AS1 significantly induced the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells. Further analysis indicated that ZEB1-AS1 could regulate the cell cycle by inhibiting the expression of G1/S transition key regulators, such as Cyclin D1 and CDK2. Furthermore, ZEB1-AS1 functioned as an important regulator of migration and invasion via activating epithelial to mesenchymal transition (EMT) through up-regulating the expression of ZEB1, MMP2, MMP9, N-cadherin, and Integrin-β1 as well as decreasing E-cadherin levels in the metastatic progression of glioma. Additionally, forced down-regulation of ZEB1-AS1 could dramatically promote apoptosis by increasing the expression level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggest that ZEB1-AS1 may serve as a new prognostic biomarker and therapeutic target of glioma. Full article
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Open AccessArticle MicroRNA-381 Regulates Chondrocyte Hypertrophy by Inhibiting Histone Deacetylase 4 Expression
Int. J. Mol. Sci. 2016, 17(9), 1377; https://doi.org/10.3390/ijms17091377
Received: 29 June 2016 / Revised: 12 August 2016 / Accepted: 16 August 2016 / Published: 23 August 2016
Cited by 9 | PDF Full-text (6891 KB) | HTML Full-text | XML Full-text
Abstract
Chondrocyte hypertrophy, regulated by Runt-related transcription factor 2 (RUNX2) and matrix metalloproteinase 13 (MMP13), is a crucial step in cartilage degeneration and osteoarthritis (OA) pathogenesis. We previously demonstrated that microRNA-381 (miR-381) promotes MMP13 expression during chondrogenesis and contributes to cartilage degeneration; however, the
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Chondrocyte hypertrophy, regulated by Runt-related transcription factor 2 (RUNX2) and matrix metalloproteinase 13 (MMP13), is a crucial step in cartilage degeneration and osteoarthritis (OA) pathogenesis. We previously demonstrated that microRNA-381 (miR-381) promotes MMP13 expression during chondrogenesis and contributes to cartilage degeneration; however, the mechanism underlying this process remained unclear. In this study, we observed divergent expression of miR-381 and histone deacetylase 4 (HDAC4), an enzyme that directly inhibits RUNX2 and MMP13 expression, during late-stage chondrogenesis of ATDC5 cells, as well as in prehypertrophic and hypertrophic chondrocytes during long bone development in E16.5 mouse embryos. We therefore investigated whether this miRNA regulates HDAC4 expression during chondrogenesis. Notably, overexpression of miR-381 inhibited HDAC4 expression but promoted RUNX2 expression. Moreover, transfection of SW1353 cells with an miR-381 mimic suppressed the activity of a reporter construct containing the 3′-untranslated region (3′-UTR) of HDAC4. Conversely, treatment with a miR-381 inhibitor yielded increased HDAC4 expression and decreased RUNX2 expression. Lastly, knockdown of HDAC4 expression resulted in increased RUNX2 and MMP13 expression in SW1353 cells. Collectively, our results indicate that miR-381 epigenetically regulates MMP13 and RUNX2 expression via targeting of HDAC4, thereby suggesting the possibilities of inhibiting miR-381 to control chondrocyte hypertrophy and cartilage degeneration. Full article
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Open AccessArticle Plasma LncRNA-ATB, a Potential Biomarker for Diagnosis of Patients with Coal Workers’ Pneumoconiosis: A Case-Control Study
Int. J. Mol. Sci. 2016, 17(8), 1367; https://doi.org/10.3390/ijms17081367
Received: 23 June 2016 / Revised: 30 July 2016 / Accepted: 11 August 2016 / Published: 22 August 2016
Cited by 6 | PDF Full-text (726 KB) | HTML Full-text | XML Full-text
Abstract
LncRNA-ATB (lncRNA was activated by transforming growth factor-β) has been reported to be involved in specific physiological and pathological processes in human diseases, and could serve as biomarkers for cancers. However, the role of lncRNA-ATB in coal workers’ pneumoconiosis (CWP) is still unknown.
[...] Read more.
LncRNA-ATB (lncRNA was activated by transforming growth factor-β) has been reported to be involved in specific physiological and pathological processes in human diseases, and could serve as biomarkers for cancers. However, the role of lncRNA-ATB in coal workers’ pneumoconiosis (CWP) is still unknown. This study aimed to investigate the association between lncRNA-ATB and CWP. Quantitative real-time polymerase chain reaction was performed to detect plasma lncRNA-ATB expression in 137 CWP patients, 72 healthy coal miners and 168 healthy controls. LncRNA-ATB was significantly upregulated in CWP (p < 0.05). Compared with the healthy controls and healthy coal miners, the odds ratios (ORs) (95% confidence interval (CI)) for CWP were 2.57 (1.52–4.33) and 2.17 (1.04–4.53), respectively. LncRNA-ATB was positively associated with transforming growth factor-β1 (TGF-β1) (r = 0.30, p = 0.003) and negative correlated with vital capacity (VC) (r = −0.18, p = 0.033) and forced vital capacity (FVC) (r = −0.18, p = 0.046) in CWP patients. Compared with healthy controls, the area under the curve (AUC) was 0.84, resulting in a 71.17% sensitivity and 88.14% specificity. When compared with healthy coal miners, the AUC was 0.83, the sensitivity and specificity were 70.07% and 86.36%, respectively. LncRNA-ATB expression is commonly increased in CWP and significantly correlates with the TGF-β1 in CWP patients. Furthermore, elevated lncRNA-ATB was associated with CWP risk and may serve as a potential biomarker for CWP. Full article
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Open AccessCommunication SMA Human iPSC-Derived Motor Neurons Show Perturbed Differentiation and Reduced miR-335-5p Expression
Int. J. Mol. Sci. 2016, 17(8), 1231; https://doi.org/10.3390/ijms17081231
Received: 24 June 2016 / Revised: 18 July 2016 / Accepted: 18 July 2016 / Published: 30 July 2016
Cited by 3 | PDF Full-text (3838 KB) | HTML Full-text | XML Full-text
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Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival Motor Neuron 1 gene, resulting in very low levels of functional Survival of Motor Neuron (SMN) protein. SMA human induced Pluripotent Stem Cells (hiPSCs) represent a useful and valid
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Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival Motor Neuron 1 gene, resulting in very low levels of functional Survival of Motor Neuron (SMN) protein. SMA human induced Pluripotent Stem Cells (hiPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. MicroRNAs (miRNAs) are often reported as playing a key role in regulating neuronal differentiation and fate specification. In this study SMA hiPSCs have been differentiated towards early motor neurons and their molecular and immunocytochemical profile were compared to those of wild type cells. Cell cycle proliferation was also evaluated by fluorescence-activated cell sorting (FACS). SMA hiPSCs showed an increased proliferation rate and also higher levels of stem cell markers. Moreover; when differentiated towards early motor neurons they expressed lower levels of NCAM and MN specific markers. The expression of miR-335-5p; already identified to control self-renewal or differentiation of mouse embryonic stem cells (mESCs); resulted to be reduced during the early steps of differentiation of SMA hiPSCs compared to wild type cells. These results suggest that we should speculate a role of this miRNA both in stemness characteristic and in differentiation efficiency of these cells. Full article
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Open AccessArticle MicroRNA-146a-5p Negatively Regulates Pro-Inflammatory Cytokine Secretion and Cell Activation in Lipopolysaccharide Stimulated Human Hepatic Stellate Cells through Inhibition of Toll-Like Receptor 4 Signaling Pathways
Int. J. Mol. Sci. 2016, 17(7), 1076; https://doi.org/10.3390/ijms17071076
Received: 30 May 2016 / Revised: 20 June 2016 / Accepted: 28 June 2016 / Published: 7 July 2016
Cited by 6 | PDF Full-text (4516 KB) | HTML Full-text | XML Full-text | Correction | Supplementary Files
Abstract
Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this
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Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB). Knockdown of IRAK1 and TRAF6 also suppressed pro-inflammatory cytokine production by inhibiting NF-κB phosphorylation. In addition, miR-146a-5p mimic blocked LPS induced TRAF6 dependent c-Jun N-terminal kinase (JNK) and Smad2 activation as well as α-SMA production. Taken together, these results suggest that miR-146a-5p suppresses pro-inflammatory cytokine secretion and cell activation of HSC through inhibition of TLR4/NF-κB and TLR4/TRAF6/JNK pathway. Full article
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Open AccessArticle miR-218 Involvement in Cardiomyocyte Hypertrophy Is Likely through Targeting REST
Int. J. Mol. Sci. 2016, 17(6), 848; https://doi.org/10.3390/ijms17060848
Received: 23 April 2016 / Revised: 10 May 2016 / Accepted: 25 May 2016 / Published: 31 May 2016
Cited by 3 | PDF Full-text (5332 KB) | HTML Full-text | XML Full-text
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MicroRNAs (miRNAs) have been identified as key players in cardiomyocyte hypertrophy, which is associated with significant risks of heart failure. However, many microRNAs are still not recognized for their functions in pathophysiological processes. In this study, we evaluated effects of miR-218 in cardiomyocyte
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MicroRNAs (miRNAs) have been identified as key players in cardiomyocyte hypertrophy, which is associated with significant risks of heart failure. However, many microRNAs are still not recognized for their functions in pathophysiological processes. In this study, we evaluated effects of miR-218 in cardiomyocyte hypertrophy using both in vitro and in vivo models. We found that miR-218 was evidently downregulated in a transverse aortic constriction (TAC) mouse model. Overexpression of miR-218 is sufficient to reduce hypertrophy, whereas the suppression of miR-218 aggravates hypertrophy in primary cardiomyocytes induced by isoprenaline (ISO). In addition, we identified RE1-silencing transcription factor (REST) as a novel target of miR-218; it negatively regulated the expression of REST in hypertrophic cardiomyocytes and the TAC model. These results showed that miR-218 plays a crucial role in cardiomyocyte hypertrophy, likely via targeting REST, suggesting a potential candidate target for interfering hypertrophy. Full article
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Open AccessReview Understanding the Functions of Long Non-Coding RNAs through Their Higher-Order Structures
Int. J. Mol. Sci. 2016, 17(5), 702; https://doi.org/10.3390/ijms17050702
Received: 15 March 2016 / Revised: 28 April 2016 / Accepted: 4 May 2016 / Published: 17 May 2016
Cited by 14 | PDF Full-text (3451 KB) | HTML Full-text | XML Full-text
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Although thousands of long non-coding RNAs (lncRNAs) have been discovered in eukaryotes, very few molecular mechanisms have been characterized due to an insufficient understanding of lncRNA structure. Therefore, investigations of lncRNA structure and subsequent elucidation of the regulatory mechanisms are urgently needed. However,
[...] Read more.
Although thousands of long non-coding RNAs (lncRNAs) have been discovered in eukaryotes, very few molecular mechanisms have been characterized due to an insufficient understanding of lncRNA structure. Therefore, investigations of lncRNA structure and subsequent elucidation of the regulatory mechanisms are urgently needed. However, since lncRNA are high molecular weight molecules, which makes their crystallization difficult, obtaining information about their structure is extremely challenging, and the structures of only several lncRNAs have been determined so far. Here, we review the structure–function relationships of the widely studied lncRNAs found in the animal and plant kingdoms, focusing on the principles and applications of both in vitro and in vivo technologies for the study of RNA structures, including dimethyl sulfate-sequencing (DMS-seq), selective 2′-hydroxyl acylation analyzed by primer extension-sequencing (SHAPE-seq), parallel analysis of RNA structure (PARS), and fragmentation sequencing (FragSeq). The aim of this review is to provide a better understanding of lncRNA biological functions by studying them at the structural level. Full article
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Open AccessReview Expression and Function of miR-155 in Diseases of the Gastrointestinal Tract
Int. J. Mol. Sci. 2016, 17(5), 709; https://doi.org/10.3390/ijms17050709
Received: 12 April 2016 / Revised: 25 April 2016 / Accepted: 3 May 2016 / Published: 11 May 2016
Cited by 7 | PDF Full-text (400 KB) | HTML Full-text | XML Full-text
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MicroRNAs (miRNAs) are a type of small noncoding RNA that can regulate the expression of target genes under physiological and pathophysiological conditions. miR-155 is a multifunctional miRNA with inflammation-related and oncogenic roles. In particular, the dysregulation of miR-155 has been strongly implicated in
[...] Read more.
MicroRNAs (miRNAs) are a type of small noncoding RNA that can regulate the expression of target genes under physiological and pathophysiological conditions. miR-155 is a multifunctional miRNA with inflammation-related and oncogenic roles. In particular, the dysregulation of miR-155 has been strongly implicated in Helicobacter pylori-related gastric disease, inflammatory bowel disease, and colorectal cancer in addition to being involved in molecular changes of important targets and signaling pathways. This review focuses on the expression and function of miR-155 during inflammation and carcinogenesis and its potential use as an effective therapeutic target for certain gastrointestinal diseases. Full article
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Open AccessArticle Mmu-miR-1894-3p Inhibits Cell Proliferation and Migration of Breast Cancer Cells by Targeting Trim46
Int. J. Mol. Sci. 2016, 17(4), 609; https://doi.org/10.3390/ijms17040609
Received: 18 March 2016 / Revised: 5 April 2016 / Accepted: 14 April 2016 / Published: 22 April 2016
PDF Full-text (5758 KB) | HTML Full-text | XML Full-text | Supplementary Files
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Breast cancer is the second leading cause of cancer death in women and the presence of metastasis significantly decreases survival. MicroRNAs are involved in tumor progression and the metastatic spreading of breast cancer. Here, we reported that a microRNA, mmu-miR-1894, significantly decreased the
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Breast cancer is the second leading cause of cancer death in women and the presence of metastasis significantly decreases survival. MicroRNAs are involved in tumor progression and the metastatic spreading of breast cancer. Here, we reported that a microRNA, mmu-miR-1894, significantly decreased the lung metastasis of 4TO7 mouse breast cancer cells by 86.7% in mouse models. Mmu-miR-1894-3p was the functional mature form of miR-1894 and significantly decreased the lung metastasis of 4TO7 cells by 90.8% in mouse models. A dual-luciferase reporter assay indicated that mmu-miR-1894-3p directly targeted the tripartite motif containing 46 (Trim46) 3′-untranslated region (UTR) and downregulated the expression of Trim46 in 4TO7 cells. Consistent with the effect of mmu-miR-1894-3p, knockdown of Trim46 inhibited the experimental lung metastasis of 4TO7 cells. Moreover, knockdown of human Trim46 also prohibited the cell proliferation, migration and wound healing of MBA-MD-231 human breast cancer cells. These results suggested that the effect of knockdown of Trim46 alone was sufficient to recapitulate the effect of mmu-miR-1894 on the metastasis of the breast cancer cells in mouse and that Trim46 was involved in the proliferation and migration of mouse and human breast cancer cells. Full article
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Open AccessEditorial Non-Coding RNAs in Cancer: An Interview with Dr. Martin Pichler
Int. J. Mol. Sci. 2016, 17(4), 605; https://doi.org/10.3390/ijms17040605
Received: 12 April 2016 / Revised: 20 April 2016 / Accepted: 20 April 2016 / Published: 21 April 2016
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Abstract
In this issue, we are pleased and honored to have an interview with Professor Martin Pichler, who is the Collection Editor for the International Journal of Molecular Sciences Topical Collection of “Regulation by Non-Coding RNAs” [1].[...] Full article
Open AccessReview Current Insights into Long Non-Coding RNAs in Renal Cell Carcinoma
Int. J. Mol. Sci. 2016, 17(4), 573; https://doi.org/10.3390/ijms17040573
Received: 22 February 2016 / Revised: 8 April 2016 / Accepted: 12 April 2016 / Published: 15 April 2016
Cited by 14 | PDF Full-text (705 KB) | HTML Full-text | XML Full-text
Abstract
Renal cell carcinoma (RCC) represents a deadly disease with rising mortality despite intensive therapeutic efforts. It comprises several subtypes in terms of distinct histopathological features and different clinical presentations. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts in the genome which vary in expression
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Renal cell carcinoma (RCC) represents a deadly disease with rising mortality despite intensive therapeutic efforts. It comprises several subtypes in terms of distinct histopathological features and different clinical presentations. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts in the genome which vary in expression levels and length and perform diverse functions. They are involved in the inititation, evolution and progression of primary cancer, as well as in the development and spread of metastases. Recently, several lncRNAs were described in RCC. This review emphasises the rising importance of lncRNAs in RCC. Moreover, it provides an outlook on their therapeutic potential in the future. Full article
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Open AccessArticle Inhibition of IFN-γ-Induced Nitric Oxide Dependent Antimycobacterial Activity by miR-155 and C/EBPβ
Int. J. Mol. Sci. 2016, 17(4), 535; https://doi.org/10.3390/ijms17040535
Received: 7 March 2016 / Revised: 25 March 2016 / Accepted: 1 April 2016 / Published: 8 April 2016
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Abstract
miR-155 (microRNA-155) is an important non-coding RNA in regulating host crucial biological regulators. However, its regulatory function in mycobacterium infection remains unclear. Our study demonstrates that miR-155 expression is significantly increased in macrophages after Mycobacterium marinum (M.m) infection. Transfection with anti-miR-155
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miR-155 (microRNA-155) is an important non-coding RNA in regulating host crucial biological regulators. However, its regulatory function in mycobacterium infection remains unclear. Our study demonstrates that miR-155 expression is significantly increased in macrophages after Mycobacterium marinum (M.m) infection. Transfection with anti-miR-155 enhances nitric oxide (NO) synthesis and decreases the mycobacterium burden, and vice versa, in interferon γ (IFN-γ) activated macrophages. More importantly, miR-155 can directly bind to the 3′UTR of CCAAT/enhancer binding protein β (C/EBPβ), a positive transcriptional regulator of nitric oxide synthase (NOS2), and regulate C/EBPβ expression negatively. Knockdown of C/EBPβ inhibit the production of nitric oxide synthase and promoted mycobacterium survival. Collectively, these data suggest that M.m-induced upregulation of miR-155 downregulated the expression of C/EBPβ, thus decreasing the production of NO and promoting mycobacterium survival, which may provide an insight into the function of miRNA in subverting the host innate immune response by using mycobacterium for its own profit. Understanding how miRNAs partly regulate microbicidal mechanisms may represent an attractive way to control tuberculosis infectious. Full article
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Open AccessReview Novel Insights into the Role of Long Noncoding RNA in Ocular Diseases
Int. J. Mol. Sci. 2016, 17(4), 478; https://doi.org/10.3390/ijms17040478
Received: 11 February 2016 / Revised: 18 March 2016 / Accepted: 18 March 2016 / Published: 31 March 2016
Cited by 9 | PDF Full-text (217 KB) | HTML Full-text | XML Full-text
Abstract
Recent advances have suggested that long noncoding RNAs (lncRNAs) are differentially expressed in ocular tissues and play a critical role in the pathogenesis of different types of eye diseases. Here, we summarize the functions and mechanisms of known aberrantly-expressed lncRNAs and present a
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Recent advances have suggested that long noncoding RNAs (lncRNAs) are differentially expressed in ocular tissues and play a critical role in the pathogenesis of different types of eye diseases. Here, we summarize the functions and mechanisms of known aberrantly-expressed lncRNAs and present a brief overview of relevant reports about lncRNAs in such ocular diseases as glaucoma, proliferative vitreoretinopathy (PVR), diabeticretinopathy (DR), and ocular tumors. We intend to highlight comprehensive studies that provide detailed data about the mechanisms of lncRNAs, their applications as diagnostic or prognostic biomarkers, and their potential therapeutic targets. Although our understanding of lncRNAs is still in its infancy, these examples may provide helpful insights into the methods by which lncRNAs interfere with ocular diseases. Full article
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Open AccessReview Crosstalk between Long Noncoding RNAs and MicroRNAs in Health and Disease
Int. J. Mol. Sci. 2016, 17(3), 356; https://doi.org/10.3390/ijms17030356
Received: 2 February 2016 / Revised: 29 February 2016 / Accepted: 2 March 2016 / Published: 11 March 2016
Cited by 42 | PDF Full-text (1118 KB) | HTML Full-text | XML Full-text
Abstract
Protein-coding genes account for only a small part of the human genome; in fact, the vast majority of transcripts are comprised of non-coding RNAs (ncRNAs) including long ncRNAs (lncRNAs) and small ncRNAs, microRNAs (miRs). Accumulating evidence indicates that ncRNAs could play critical roles
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Protein-coding genes account for only a small part of the human genome; in fact, the vast majority of transcripts are comprised of non-coding RNAs (ncRNAs) including long ncRNAs (lncRNAs) and small ncRNAs, microRNAs (miRs). Accumulating evidence indicates that ncRNAs could play critical roles in regulating many cellular processes which are often implicated in health and disease. For example, ncRNAs are aberrantly expressed in cancers, heart diseases, and many other diseases. LncRNAs and miRs are therefore novel and promising targets to be developed into biomarkers for diagnosis and prognosis as well as treatment options. The interaction between lncRNAs and miRs as well as its pathophysiological significance have recently been reported. Mechanistically, it is believed that lncRNAs exert “sponge-like” effects on various miRs, which subsequently inhibits miR-mediated functions. This crosstalk between two types of ncRNAs frequently contributes to the pathogenesis of the disease. In this review, we provide a summary of the recent studies highlighting the interaction between these ncRNAs and the effects of this interaction on disease pathogenesis and regulation. Full article
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