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: Small nucleolar RNAs (snoRNAs) have long been considered important but unglamorous elements in the production of the protein synthesis machinery of the cell, and their dysfunction could contribute to oncogenesis in previously unsuspected ways.
Abstract: Small nucleolar RNAs (snoRNAs) have long been considered important but unglamorous elements in the production of the protein synthesis machinery of the cell. Recently, however, several independent lines of evidence have indicated that these non-coding RNAs might have crucial roles in controlling cell behaviour, and snoRNA dysfunction could consequently contribute to oncogenesis in previously unsuspected ways.
285 citations
TL;DR: In this paper, the Megaplex reverse transcription format of the stem-loop primer-based real-time quantitative polymerase chain reaction (RT-qPCR) approach was used to quantify miRNA expression.
Abstract: MicroRNAs (miRNAs) are an emerging class of small non-coding RNAs implicated in a wide variety of cellular processes. Research in this field is accelerating, and the growing number of miRNAs emphasizes the need for high-throughput and sensitive detection methods. Here we present the successful evaluation of the Megaplex reverse transcription format of the stem-loop primer-based real-time quantitative polymerase chain reaction (RT-qPCR) approach to quantify miRNA expression. The Megaplex reaction provides simultaneous reverse transcription of 450 mature miRNAs, ensuring high-throughput detection. Further, the introduction of a complementary DNA pre-amplification step significantly reduces the amount of input RNA needed, even down to single-cell level. To evaluate possible pre-amplification bias, we compared the expression of 384 miRNAs in three different cancer cell lines with Megaplex RT, with or without an additional pre-amplification step. The normalized Cq values of all three sample pairs showed a good correlation with maintenance of differential miRNA expression between the cell lines. Moreover, pre-amplification using 10 ng of input RNA enabled the detection of miRNAs that were undetectable when using Megaplex alone with 400 ng of input RNA. The high specificity of RT-qPCR together with a superior sensitivity makes this approach the method of choice for high-throughput miRNA expression profiling.
284 citations
TL;DR: It is found that functional SNP rs11614913 in miR-196a2 could also contribute to lung cancer susceptibility, and is evaluated in a case-control study of incident lung cancer patients and 1,035 cancer-free controls in a Chinese population.
Abstract: microRNAs (miRNA) are a new class of non-protein-coding, small RNAs that function as tumor suppressors or oncogenes. They participate in diverse biological pathways and function as gene regulators. Recently, we conducted a survey of common single nucleotide polymorphisms (SNP) in miRNA sequences and reported that, among four SNPs (rs2910164, rs2292832, rs11614913, and rs3746444) in pre-miRNAs, rs11614913 in miR-196a2 might affect mature miR-196a expression and target mRNA-binding activity and was significantly associated with non-small cell lung cancer survival. However, it remains largely unknown whether miRNA SNPs may alter lung cancer susceptibility. In the current study, we evaluated associations between the above four SNPs in pre-miRNAs and lung cancer susceptibility in a case-control study of 1,058 incident lung cancer patients and 1,035 cancer-free controls in a Chinese population. We found that miR-196a2 rs11614913 variant homozygote CC was associated with approximately 25% significantly increased risk of lung cancer compared with their wild-type homozygote TT and heterozygote TC (odds ratio, 1.25; 95% confidence interval, 1.01-1.54). However, no significant effects were observed on the association between the other three SNPs and lung cancer risk. These findings suggest that functional SNP rs11614913 in miR-196a2 could also contribute to lung cancer susceptibility.
284 citations
TL;DR: A small noncoding RNA signature in microvesicles isolated from GBM patient serum is uncovered that could be used as a fast and reliable differential diagnostic biomarker.
Abstract: Background. Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults, and its prognosis remains dismal despite intensive research and therapeutic advances. Diagnostic biomarkers would be clinically meaningful to allow for early detection of the tumor and for those cases in which surgery is contraindicated or biopsy results are inconclusive. Recent findings show that GBM cells release microvesicles that contain a select subset of cellular proteins and RNA. The aim of this hypothesis-generating study was to assess the diagnostic potential of miRNAs found in microvesicles isolated from the serum of GBM patients. Methods. To control disease heterogeneity, we used patients with newly diagnosed GBM. In the discovery stage, PCR-based TaqMan Low Density Arrays followed by individual quantitative reverse transcriptase polymerase chain reaction were used to test the differences in the miRNA expression levels of serum microvesicles among 25 GBM patients and healthy controls paired by age and sex. The detected noncoding RNAs were then validated in another 50 GBM patients. Results. We found that the expression levels of 1 small noncoding RNA (RNU6-1) and 2 microRNAs (miR-320 and miR-574-3p) were significantly associated with a GBM diagnosis. In addition, RNU6-1 was consistently an independent predictor of a GBM diagnosis. Conclusions. Altogether our results uncovered a small noncoding RNA signature in microvesicles isolated from GBM patient serum that could be used as a fast and reliable differential diagnostic biomarker.
284 citations
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TL;DR: The graphical output of the program provides an overview of the parts of the pathway modulated by microRNAs, facilitating the interpretation and presentation of the analysis results.
Abstract: Summary: DIANA-mirPath is a web-based computational tool developed to identify molecular pathways potentially altered by the expression of single or multiple microRNAs. The software performs an enrichment analysis of multiple microRNA target genes comparing each set of microRNA targets to all known KEGG pathways. The combinatorial effect of co-expressed microRNAs in the modulation of a given pathway is taken into account by the simultaneous analysis of multiple microRNAs. The graphical output of the program provides an overview of the parts of the pathway modulated by microRNAs, facilitating the interpretation and presentation of the analysis results.
Availability: The software is available at http://microrna.gr/mirpath and is free for all users with no login or download requirement.
Contact:[email protected] or [email protected]
284 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