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.
Citations
More filters
TL;DR: It is shown here that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity and established the measurement of tumor-derived mi RNAs in serum or plasma as an important approach for the blood-based detection of human cancer.
Abstract: Improved approaches for the detection of common epithelial malignancies are urgently needed to reduce the worldwide morbidity and mortality caused by cancer. MicroRNAs (miRNAs) are small (≈22 nt) regulatory RNAs that are frequently dysregulated in cancer and have shown promise as tissue-based markers for cancer classification and prognostication. We show here that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity. miRNAs originating from human prostate cancer xenografts enter the circulation, are readily measured in plasma, and can robustly distinguish xenografted mice from controls. This concept extends to cancer in humans, where serum levels of miR-141 (a miRNA expressed in prostate cancer) can distinguish patients with prostate cancer from healthy controls. Our results establish the measurement of tumor-derived miRNAs in serum or plasma as an important approach for the blood-based detection of human cancer.
7,296 citations
Journal Article•
TL;DR: The causes of the widespread differential expression of miRNA genes in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the miRNA processing machinery as discussed by the authors.
Abstract: MicroRNA (miRNA) alterations are involved in the initiation and progression of human cancer. The causes of the widespread differential expression of miRNA genes in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the miRNA processing machinery. MiRNA-expression profiling of human tumours has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify miRNA genes that might represent downstream targets of activated oncogenic pathways, or that target protein- coding genes involved in cancer.
6,306 citations
TL;DR: This Review summarizes the current understanding of the mechanistic aspects of microRNA-induced repression of translation and discusses some of the controversies regarding different modes of micro RNA function.
Abstract: MicroRNAs constitute a large family of small, approximately 21-nucleotide-long, non-coding RNAs that have emerged as key post-transcriptional regulators of gene expression in metazoans and plants. In mammals, microRNAs are predicted to control the activity of approximately 30% of all protein-coding genes, and have been shown to participate in the regulation of almost every cellular process investigated so far. By base pairing to mRNAs, microRNAs mediate translational repression or mRNA degradation. This Review summarizes the current understanding of the mechanistic aspects of microRNA-induced repression of translation and discusses some of the controversies regarding different modes of microRNA function.
4,973 citations
TL;DR: It is demonstrated that miRNAs are present in the serum and plasma of humans and other animals such as mice, rats, bovine fetuses, calves, and horses, and can serve as potential biomarkers for the detection of various cancers and other diseases.
Abstract: Dysregulated expression of microRNAs (miRNAs) in various tissues has been associated with a variety of diseases, including cancers. Here we demonstrate that miRNAs are present in the serum and plasma of humans and other animals such as mice, rats, bovine fetuses, calves, and horses. The levels of miRNAs in serum are stable, reproducible, and consistent among individuals of the same species. Employing Solexa, we sequenced all serum miRNAs of healthy Chinese subjects and found over 100 and 91 serum miRNAs in male and female subjects, respectively. We also identified specific expression patterns of serum miRNAs for lung cancer, colorectal cancer, and diabetes, providing evidence that serum miRNAs contain fingerprints for various diseases. Two non-small cell lung cancer-specific serum miRNAs obtained by Solexa were further validated in an independent trial of 75 healthy donors and 152 cancer patients, using quantitative reverse transcription polymerase chain reaction assays. Through these analyses, we conclude that serum miRNAs can serve as potential biomarkers for the detection of various cancers and other diseases.
4,184 citations
TL;DR: Dysregulation of these ncRNAs is being found to have relevance not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases, and there is great interest in therapeutic strategies to counteract these perturbations.
Abstract: The role of non-coding RNAs (ncRNAs) in disease is best understood for microRNAs in cancer. However, there is increasing interest in the disease-related roles of other ncRNAs — including piRNAs, snoRNAs, T-UCRs and lncRNAs — and in using this knowledge for therapy.
4,016 citations
References
More filters
TL;DR: A new computational method which is designed to identify microRNA target sites and finds that a number of key developmental body patterning genes such as hairy and fushi-tarazu are likely to be translationally regulated by microRNAs.
Abstract: Recent experiments have shown that the genomes of organisms such as worm, fly, human and mouse encode hundreds of microRNA genes. Many of these microRNAs are thought to regulate the translational expression of other genes by binding to partially complementary sites in messenger RNAs. Phenotypic and expression analysis suggest an important role of microRNAs during development. Therefore, it is of fundamental importance to identify microRNA targets. However, no experimental or computational high-throughput method for target site identification in animals has been published yet. Our main result is a new computational method which is designed to identify microRNA target sites. This method recovers with high specificity known microRNA target sites which previously have been defined experimentally. Based on these results, we present a simple model for the mechanism of microRNA target site recognition. Our model incorporates both kinetic and thermodynamic components of target recognition. When we applied our method to a set of 74 Drosophila melanogaster microRNAs, searching 3' UTR sequences of a predefined set of fly mRNAs for target sites which were evolutionary conserved between Drosophila melanogaster and Drosophila pseudoobscura, we found that a number of key developmental body patterning genes such as hairy and fushi-tarazu are likely to be translationally regulated by microRNAs.
228 citations
TL;DR: Screening of 33 cases of MDS with normal karyotype failed to detect a monoallelic deletion of PI-PLCb1 gene, which seems to indicate that the cryptic deletion that appears to be associated with very short survival is a rare event in MDS and thus of limited utility as a prognostic marker.
Abstract: sion. An abnormal karyotype developed in eight of our patients, usually preceding, and in every case associated with, leukemic evolution as observed in seven of 19 patients developing AML and one patient developing RAEB with monosomy 7. In summary, screening of 33 cases of MDS with normal karyotype failed to detect a monoallelic deletion of PI-PLCb1 gene. All FAB classes and IPSS risk groups were represented. This seems to indicate that the cryptic deletion that appears to be associated with very short survival is a rare event in MDS and thus of limited utility as a prognostic marker. This letter is also a call to other groups to share their experience with the use of this marker.
224 citations
TL;DR: A conceptual framework for miRNA action in the context of creating cellular diversity in a developing organism is provided, and the conceptual similarity of TF- and miRNAs-mediated control of gene expression is emphasized.
209 citations
TL;DR: The consequences of mutations of a novel locus, named bantam, whose product is involved in the regulation of growth in Drosophila are reported, and epistasis and genetic interaction analyses indicate that bantam and cyclinD-cdk4 operate independently.
Abstract: We report here the consequences of mutations of a novel locus, named bantam, whose product is involved in the regulation of growth in Drosophila. bantam mutant animals are smaller than wild type, due to a reduction in cell number but not cell size, and do not have significant disruptions in patterning. Conversely, overexpression of the bantam product using the EP element EP(3)3622 causes overgrowth of wing and eye tissue. Overexpression in clones of cells results in an increased rate of cell proliferation and a matched increase in cellular growth rate, such that the resulting tissue is composed of more cells of a size comparable to wild type. These effects are strikingly similar to those associated with alterations in the activity of the cyclinD-cdk4 complex. However, epistasis and genetic interaction analyses indicate that bantam and cyclinD-cdk4 operate independently. Thus, the bantam locus represents a novel regulator of tissue growth.
209 citations
TL;DR: The bidentate RNase III Dicer cleaves microRNA precursors to generate the 21-23 nt long mature RNAs, which fit the minihelix export motif and are thus likely exported by this pathway.
Abstract: The bidentate RNase III Dicer cleaves microRNA precursors to generate the 21-23 nt long mature RNAs. These precursors are 60-80 nt long, they fold into a characteristic stem-loop structure and they are generated by an unknown mechanism. To gain insights into the biogenesis of microRNAs, we have characterized the precise 5' and 3' ends of the let-7 precursors in human cells. We show that they harbor a 5'-phosphate and a 3'-OH and that, remarkably, they contain a 1-4 nt 3' overhang. These features are characteristic of RNase III cleavage products. Since these precursors are present in both the nucleus and the cytoplasm of human cells, our results suggest that they are generated in the nucleus by the nuclear RNase III. Additionally, these precursors fit the minihelix export motif and are thus likely exported by this pathway.
203 citations