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Journal Article

Oncomirs : microRNAs with a role in cancer

01 Jan 2007-Nature Reviews Genetics (Nature Publishing Group)-
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.
Citations
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Journal ArticleDOI
02 May 2007-JAMA
TL;DR: Pancreatic cancer may have a distinct miRNA expression pattern that may differentiate it from normal pancreas and chronic pancreatitis, but these findings need to be validated in other study populations.
Abstract: ContextWhile global microRNA (miRNA) expression patterns of many embryologic, physiologic, and oncogenic processes have been described, description of the role of miRNAs in ductal adenocarcinoma of the pancreas is lacking.ObjectiveTo define the expression pattern of miRNAs in pancreatic cancer and compare it with those of normal pancreas and chronic pancreatitis.Design and SettingSpecimens were obtained at a National Cancer Institute–designated comprehensive cancer center from patients with ductal adenocarcinoma of the pancreas (n = 65) or chronic pancreatitis (n = 42) (January 2000-December 2005). All patients underwent curative pancreatectomy; those with pancreatic cancer were chemotherapy-naive. RNA harvested from resected pancreatic cancers and matched benign adjacent pancreatic tissue as well as from chronic pancreatitis specimens was hybridized to miRNA microarrays.Main Outcome MeasuresIdentification of differentially expressed miRNAs that could differentiate pancreatic cancer from normal pancreas, chronic pancreatitis, or both, as well as a pattern of miRNA expression predictive of long-term (>24 months) survival. Significance of Analysis of Microarrays and Prediction of Analysis of Microarrays were undertaken to identify miRNAs predictive of tissue type and prognosis. P values were calculated by t test, adjusted for multiple testing. Kaplan-Meier survival curves were constructed using mean miRNA expression (high vs low) as threshold and compared by log-rank analysis.ResultsTwenty-one miRNAs with increased expression and 4 with decreased expression were identified that correctly differentiated pancreatic cancer from benign pancreatic tissue in 90% of samples by cross validation. Fifteen overexpressed and 8 underexpressed miRNAs differentiated pancreatic cancer from chronic pancreatitis with 93% accuracy. A subgroup of 6 miRNAs was able to distinguish long-term survivors with node-positive disease from those dying within 24 months. Finally, high expression of miR-196a-2 was found to predict poor survival (median, 14.3 months [95% confidence interval, 12.4-16.2] vs 26.5 months [95% confidence interval, 23.4-29.6]; P = .009).ConclusionsPancreatic cancer may have a distinct miRNA expression pattern that may differentiate it from normal pancreas and chronic pancreatitis. miRNA expression patterns may be able to distinguish between long- and short-term survivors, but these findings need to be validated in other study populations.

1,171 citations

Journal ArticleDOI
TL;DR: The evidence for a role of miR-34a and miR/c in the apoptotic response of normal and tumor cells is surveyed and has been linked to resistance against apoptosis induced by p53 activating agents used in chemotherapy.
Abstract: Recently, the transcription factor encoded by tumor suppressor gene p53 was shown to regulate the expression of microRNAs. The most significant induction by p53 was observed for the microRNAs miR-34a and miR-34b/c, which turned out to be direct p53 target genes. Ectopic miR-34 expression induces apoptosis, cell-cycle arrest or senescence. In many tumor types the promoters of the miR-34a and the miR-34b/c genes are subject to inactivation by CpG methylation. MiR-34a resides on 1p36 and is commonly deleted in neuroblastomas. Furthermore, the loss of miR-34 expression has been linked to resistance against apoptosis induced by p53 activating agents used in chemotherapy. In this review, the evidence for a role of miR-34a and miR-34b/c in the apoptotic response of normal and tumor cells is surveyed.

1,146 citations

Journal ArticleDOI
23 Jul 2009-Nature
TL;DR: This study reveals a previously unrecognized function of p53 in miRNA processing, which may underlie key aspects of cancer biology, and suggests that transcription-independent modulation of miRNA biogenesis is intrinsically embedded in a tumour suppressive program governed by p53.
Abstract: MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression, involved in diverse physiological and pathological processes. Although miRNAs can function as both tumour suppressors and oncogenes in tumour development, a widespread downregulation of miRNAs is commonly observed in human cancers and promotes cellular transformation and tumorigenesis. This indicates an inherent significance of small RNAs in tumour suppression. However, the connection between tumour suppressor networks and miRNA biogenesis machineries has not been investigated in depth. Here we show that a central tumour suppressor, p53, enhances the post-transcriptional maturation of several miRNAs with growth-suppressive function, including miR-16-1, miR-143 and miR-145, in response to DNA damage. In HCT116 cells and human diploid fibroblasts, p53 interacts with the Drosha processing complex through the association with DEAD-box RNA helicase p68 (also known as DDX5) and facilitates the processing of primary miRNAs to precursor miRNAs. We also found that transcriptionally inactive p53 mutants interfere with a functional assembly between Drosha complex and p68, leading to attenuation of miRNA processing activity. These findings suggest that transcription-independent modulation of miRNA biogenesis is intrinsically embedded in a tumour suppressive program governed by p53. Our study reveals a previously unrecognized function of p53 in miRNA processing, which may underlie key aspects of cancer biology.

1,138 citations

Journal ArticleDOI
TL;DR: The tumor suppressor protein Programmed Cell Death 4 (PDCD4) is regulated by miR-21 and it is demonstrated that PDCD4 is a functionally important target for mi R-21 in breast cancer cells.

1,107 citations

Journal ArticleDOI
TL;DR: Findings establish a role for microRNAs in non–cell-autonomous Myc-induced tumor phenotypes and suggest that Ras-only cells with a miR-17-92–encoding retrovirus reduced Tsp1 and CTGF levels and formed larger, better-perfused tumors.
Abstract: Human adenocarcinomas commonly harbor mutations in the KRAS and MYC proto-oncogenes and the TP53 tumor suppressor gene. All three genetic lesions are potentially pro-angiogenic, as they sustain production of vascular endothelial growth factor (VEGF). Yet Kras-transformed mouse colonocytes lacking p53 formed indolent, poorly vascularized tumors, whereas additional transduction with a Myc-encoding retrovirus promoted vigorous vascularization and growth. In addition, VEGF levels were unaffected by Myc, but enhanced neovascularization correlated with downregulation of anti-angiogenic thrombospondin-1 (Tsp1) and related proteins, such as connective tissue growth factor (CTGF). Both Tsp1 and CTGF are predicted targets for repression by the miR-17-92 microRNA cluster, which was upregulated in colonocytes coexpressing K-Ras and c-Myc. Indeed, miR-17-92 knockdown with antisense 2′-O-methyl oligoribonucleotides partly restored Tsp1 and CTGF expression; in addition, transduction of Ras-only cells with a miR-17-92–encoding retrovirus reduced Tsp1 and CTGF levels. Notably, miR-17-92–transduced cells formed larger, better-perfused tumors. These findings establish a role for microRNAs in non–cell-autonomous Myc-induced tumor phenotypes.

1,093 citations

References
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Journal ArticleDOI
23 Jan 2004-Cell
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

Journal ArticleDOI
03 Dec 1993-Cell
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

Journal ArticleDOI
09 Jun 2005-Nature
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

Journal ArticleDOI
26 Dec 2003-Cell
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

Journal ArticleDOI
25 Sep 2003-Nature
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