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: 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
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TL;DR: It is demonstrated that miR-155/BIC is highly expressed in pediatric BL but not in other hematologic malignancies, for example, pre-B/common or T-cell leukemia.
Abstract: In a recent issue of Genes, Chromosomes & Cancer, van den Berg et al. (2003) reported on the high expression of human BIC RNA in Hodgkin lymphoma by means of the serial analysis of gene expression (SAGE) technique. In addition, using a combination of RNA in situ hybridization and immunostaining, they found that the expression of BIC is specific for Reed–Sternberg (RS) cells and that the BIC transcripts were in the nuclei of the RS cells. In contrast to their findings in Hodgkin lymphoma, an analysis of 43 cases of non-Hodgkin lymphoma (NHL; 15 follicular lymphomas, 7 diffuse large B-cell lymphomas, 9 Burkitt lymphomas, 7 anaplastic large cell lymphomas, and 5 T-cell-rich B-cell lymphomas) did not reveal any remarkable up-regulation of BIC expression, although one case of Burkitt lymphoma (BL) showed weak expression of BIC in a minority of its tumor cells. The BIC locus was originally identified as a common retroviral integration site in avian-leukosis virus–induced B–cell lymphomas (Clurman and Hayward, 1989; Tam et al., 1997). It should be stressed that the human BIC gene encodes a microRNA, miR-155. This microRNA is encoded by nucleotides 241–262 of BIC, which spans 1,421 bp in total and is on chromosome 21 (GenBank accession number: AF402776). MicroRNAs (miRNAs) are an abundant class of noncoding RNAs that interact with coding mRNA and trigger either translation repression or direct RNA cleavage via RNA interference, depending on the degree of complementarity with the specific target mRNA (Ambros, 2001; Lagos-Quintana et al., 2001; Ruvkun, 2001; Lai, 2002; Pasquinelli, 2002; Ambros et al., 2003; Lagos-Quintana et al., 2003). Mature miRNAs are 21–23 nt long and are excised from an approximately 60to 80-nt double-stranded RNA hairpin by Dicer RNase III (Hutvagner et al., 2001). In the last 2 years, more than 200 human microRNA genes have been described, but the prediction and validation of their target mRNAs by computerized means and experimental approaches is a tantalizing and still unresolved task (Ambros et al., 2003). Apart from this open question, it was recently hypothesized that microRNA genes might play an important role in oncogenesis (McManus, 2003). We support the idea advanced by van den Berg et al. that BIC might play a role in the selection of B cells, but here we also extend their data by demonstrating that miR-155/BIC is highly expressed in pediatric BL but not in other hematologic malignancies, for example, pre-B/common or T-cell leukemia. The conditio sine qua non for the development of BL is activation of the MYC oncogene, mostly by chromosomal translocations in which MYC is juxtaposed to an immunoglobulin enhancer. On the other hand, there is a body of evidence that the activation of MYC alone is not sufficient for full malignancy. Providing support for this contention was the demonstration that MYC cooperates with BMI1, PIM1, RAF, BCL2, or, as shown in a very recent report, with the Werner syndrome protein WRN (Grandori et al., 2003) We analyzed tumor cells from 21 children (ages 2–13 years, with a median age of 6 years) with BL (n 11), common/pre-B acute lymphoblastic leukemia (ALL; n 6), or T-cell ALL (n 4). In all cases selected, the proportion of tumor cells was 80% or greater. The presence of an IGH/MYC rearrangement was demonstrated by long-distance polymerase chain reaction (PCR) in all BL cases, whereas neither the common/pre-B nor T-cell ALLs had such a recombination (Busch et al., unpublished data). All patients were treated according to the NHL-BFM 90, 95, or the ALL-BFM 90, 95 multicenter therapy study (Reiter et al., 1999; Schrappe et al., 2000). Immunophenotyping was done according to standard procedures (Ludwig et al., 1994). Informed parental consent was obtained in all cases. RNA isolated from peripheral blood from 11 healthy volunteers served as an additional control.
635 citations
TL;DR: The results suggest that miRNAs, and the closely similar small interfering RNAs, cannot totally discriminate between RNA targets differing by a single nucleotide.
Abstract: Most eukaryotes encode a substantial number of small noncoding RNAs termed micro RNAs (miRNAs). Previously, we have demonstrated that miR-30, a 22-nucleotide human miRNA, can be processed from a longer transcript bearing the proposed miR-30 stem-loop precursor and can translationally inhibit an mRNA-bearing artificial target sites. We also demonstrated that the miR-30 precursor stem can be substituted with a heterologous stem, which can be processed to yield novel miRNAs and can block the expression of endogenous mRNAs. Here, we show that a second human miRNA, termed miR-21, can also be effectively expressed when its precursor forms part of a longer mRNA. For both miR-30 and miR-21, mature miRNA production was highly dependent on the integrity of the precursor RNA stem, although the underlying sequence had little effect. In contrast, the sequence of the terminal loop affected miRNA production only moderately. Processing of the initial, miR-30-containing transcript led to the production of not only mature miR-30 but also to the largely nuclear excision of an ∼65-nucleotide RNA that is likely to represent an important intermediate in miR-30 processing. Consistent with this hypothesis, mutations that affected mature miR-30 production inhibited expression of this miR-30 pre-miRNA to an equivalent degree. Although point mutations could block the ability of both miR-30 and miR-21 to inhibit the translation of mRNAs bearing multiple artificial miRNA target sites, single point mutations only attenuated the miRNA-mediated inhibition of genes bearing single, fully complementary targets. These results suggest that miRNAs, and the closely similar small interfering RNAs, cannot totally discriminate between RNA targets differing by a single nucleotide.
597 citations
TL;DR: The results of this study indicate that Dicer exerts its function on mouse embryonic angiogenesis probably through its role in the processing of microRNAs that regulate the expression levels of some critical angiogenic regulators in the cell.
556 citations
TL;DR: It is shown that loss of Dicer results in cell death with the accumulation of abnormal mitotic cells that show premature sister chromatid separation and that Dicer-related RNA interference machinery is involved in the formation of the heterochromatin structure in higher vertebrate cells.
Abstract: RNA interference is an evolutionarily conserved gene-silencing pathway in which the nuclease Dicer cleaves double-stranded RNA into small interfering RNAs1. The biological function of the RNAi-related pathway in vertebrate cells is not fully understood. Here, we report the generation of a conditional loss-of-function Dicer mutant in a chicken–human hybrid DT40 cell line that contains human chromosome 21. We show that loss of Dicer results in cell death with the accumulation of abnormal mitotic cells that show premature sister chromatid separation. Aberrant accumulation of transcripts from α-satellite sequences, which consist of human centromeric repeat DNAs, was detected in Dicer-deficient cells. Immunocytochemical analysis revealed abnormalities in the localization of two heterochromatin proteins, Rad21 cohesin protein and BubR1 checkpoint protein, but the localization of core kinetochore proteins such as centromere protein (CENP)-A and -C was normal. We conclude that Dicer-related RNA interference machinery is involved in the formation of the heterochromatin structure in higher vertebrate cells.
514 citations
TL;DR: It is demonstrated that wild-type let-7 microRNA binds in vitro to RNA from the lin-41 3'UTR, providing the first experimental evidence for an animal miRNA binding directly to its validated target in vivo.
Abstract: Caenorhabditis elegans let-7, a founding member of the microRNA family, is predicted to bind to six sites in the 3′UTR of the mRNA of its target gene, lin-41, to down-regulate LIN-41. Here, we demonstrate that wild-type let-7 microRNA binds in vitro to RNA from the lin-41 3′UTR. This interaction is dependent on two conserved let-7 complementary sites (LCSs). A 27-nucleotide sequence between the LCSs is also necessary for down-regulation in vivo. LCS mutations compensatory to the lesion in let-7(n2853) can partially restore lin-41 3′UTR function in a let-7(n2853) background, providing the first experimental evidence for an animal miRNA binding directly to its validated target in vivo.
489 citations