Journal Article•
Oncomirs : microRNAs with a role in cancer
TL;DR: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators as discussed by the authors, and have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.
Abstract: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators. They regulate diverse biological processes, and bioinformatic data indicates that each miRNA can control hundreds of gene targets, underscoring the potential influence of miRNAs on almost every genetic pathway. Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes. miRNAs have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.
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TL;DR: A core module of heterochronic genes—lin-28, lin-41, let-7, and lin-4/mir-125—acts as an ancient regulatory switch for differentiation in stem cells (and in some cancers), illustrating that nematode seam cells mirror miRNA regulatory networks in mammalian stem cells during both normal development and cancer.
Abstract: MicroRNAs (miRNAs) were first discovered in genetic screens for regulators of developmental timing in the stem-cell-like seam cell lineage in Caenorhabditis elegans. As members of the heterochronic pathway, the lin-4 and let-7 miRNAs are required in the seam cells for the correct progression of stage-specific events and to ensure that cell cycle exit and terminal differentiation occur at the correct time. Other heterochronic genes such as lin-28 and lin-41 are direct targets of the lin-4 and let-7 miRNAs. Recent findings on the functions of the let-7 and lin-4/mir-125 miRNA families and lin-28 and lin-41 orthologs from a variety of organisms suggest that core elements of the heterochronic pathway are retained in mammalian stem cells and development. In particular, these genes appear to form bistable switches via double-negative feedback loops in both nematode and mammalian stem cell development, the functional relevance of which is finally becoming clear. let-7 inhibits stem cell self-renewal in both normal and cancer stem cells of the breast and acts as a tumor suppressor in lung and breast cancer. let-7 also promotes terminal differentiation at the larval to adult transition in both nematode stem cells and fly wing imaginal discs and inhibits proliferation of human lung and liver cancer cells. Conversely, LIN-28 is a highly specific embryonic stem cell marker and is one of four “stemness” factors used to reprogram adult fibroblasts into induced pluripotent stem cells; furthermore, lin-28 is oncogenic in hepatocellular carcinomas. Therefore, a core module of heterochronic genes—lin-28, lin-41, let-7, and lin-4/mir-125—acts as an ancient regulatory switch for differentiation in stem cells (and in some cancers), illustrating that nematode seam cells mirror miRNA regulatory networks in mammalian stem cells during both normal development and cancer.
130 citations
TL;DR: In this study, the high-risk subtype HPV-16 E6 oncoprotein was found to decrease the expression of miR-23b, increase theexpression of uPA, and thus induce the migration of human cervical carcinoma SiHa and CaSki cells.
Abstract: Deregulation of microRNA (miRNA or miR) expression in human cervical cancer is associated frequently with human papillomavirus (HPV) integration. miR-23b is often downregulated in HPV-associated cervical cancer. Interestingly, urokinase-type plasminogen activator (uPA), the miR-23b target, is detected in cervical cancer, but not in normal cervical tissues. Thus, the importance of miR-23b and uPA in HPV-associated cervical cancer development is investigated. In this study, the high-risk subtype HPV-16 E6 oncoprotein was found to decrease the expression of miR-23b, increase the expression of uPA, and thus induce the migration of human cervical carcinoma SiHa and CaSki cells. uPA is the target gene for miR-23b as the miR repressed uPA expression and interacted with the 3'-untranslated region of uPA mRNA. The tumor suppressor p53 is known to be inactivated by HPV-16 E6. A consensus p53 binding site is detected in the promoter region of miR-23b, whereas p53 trans-activated and also interacted with the miR's promoter. Therefore, p53 is believed to mediate the HPV-16 E6 downregulation of miR-23b. From the above, miR-23b/uPA are confirmed to be involved in HPV-16 E6-associated cervical cancer development.
130 citations
TL;DR: In this paper, the authors demonstrate that miRNAs can be antagonized in vivo by oligonucleotides composed of high-affinity nucleotide mimics, which can be used to specifically inhibit miRNA function.
Abstract: MicroRNAs (miRNAs) are a novel class of endogenous non-coding single-stranded RNAs, which regulate gene expression post-transcriptionally by base pairing with their target mRNAs. So far > 5000 miRNA entries have been registered and miRNAs have been implicated in most, if not all, central cellular processes and several diseases. As the mechanism of action for miRNA regulation of target mRNAs is mediated by Watson-Crick base pairing, antisense oligonucleotides targeting the miRNAs appear as an obvious choice to specifically inhibit miRNA function. Indeed, miRNAs can be antagonized in vivo by oligonucleotides composed of high-affinity nucleotide mimics. Lessons learned from traditional antisense strategies and small-interfering RNA approaches, that is from potent nucleotide mimics, design rules, pharmacokinetics, administration and safety issues, are likely to pave the way for future clinical trials of miRNA-antagonizing oligonucleotides.
130 citations
TL;DR: The deregulation of miR-99 family contributes to the tumorigenesis of HNSCC, in part by targeting IGF1R and mTOR signaling pathways.
130 citations
TL;DR: A novel role of let-7/HMGA2 axis is found in regulating the balance of osteogenesis and adipogenesis of MSCs and can be used as a novel therapeutic target for disorders that are associated with bone loss and adipocyte accumulation.
Abstract: Bone and fat cells share a common progenitor, stromal/mesenchymal stem cells (MSCs), that can differentiate into osteoblasts or adipocytes. Osteogenesis and adipogenesis of MSCs maintain homeostasi...
130 citations
References
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TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.
32,946 citations
TL;DR: Two small lin-4 transcripts of approximately 22 and 61 nt were identified in C. elegans and found to contain sequences complementary to a repeated sequence element in the 3' untranslated region (UTR) of lin-14 mRNA, suggesting that lin- 4 regulates lin- 14 translation via an antisense RNA-RNA interaction.
11,932 citations
TL;DR: A new, bead-based flow cytometric miRNA expression profiling method is used to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers, and finds the miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours.
Abstract: Recent work has revealed the existence of a class of small non-coding RNA species, known as microRNAs (miRNAs), which have critical functions across various biological processes. Here we use a new, bead-based flow cytometric miRNA expression profiling method to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers. The miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours. We observe a general downregulation of miRNAs in tumours compared with normal tissues. Furthermore, we were able to successfully classify poorly differentiated tumours using miRNA expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. These findings highlight the potential of miRNA profiling in cancer diagnosis.
9,470 citations
TL;DR: The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
5,246 citations
TL;DR: The two RNase III proteins, Drosha and Dicer, may collaborate in the stepwise processing of miRNAs, and have key roles in miRNA-mediated gene regulation in processes such as development and differentiation.
Abstract: Hundreds of small RNAs of approximately 22 nucleotides, collectively named microRNAs (miRNAs), have been discovered recently in animals and plants. Although their functions are being unravelled, their mechanism of biogenesis remains poorly understood. miRNAs are transcribed as long primary transcripts (pri-miRNAs) whose maturation occurs through sequential processing events: the nuclear processing of the pri-miRNAs into stem-loop precursors of approximately 70 nucleotides (pre-miRNAs), and the cytoplasmic processing of pre-miRNAs into mature miRNAs. Dicer, a member of the RNase III superfamily of bidentate nucleases, mediates the latter step, whereas the processing enzyme for the former step is unknown. Here we identify another RNase III, human Drosha, as the core nuclease that executes the initiation step of miRNA processing in the nucleus. Immunopurified Drosha cleaved pri-miRNA to release pre-miRNA in vitro. Furthermore, RNA interference of Drosha resulted in the strong accumulation of pri-miRNA and the reduction of pre-miRNA and mature miRNA in vivo. Thus, the two RNase III proteins, Drosha and Dicer, may collaborate in the stepwise processing of miRNAs, and have key roles in miRNA-mediated gene regulation in processes such as development and differentiation.
5,191 citations