MicroRNAs directing siRNA biogenesis.
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We report on the location of 283 miRNAs in the human genome in relation to copy number changes in three distinct types of tumours: prostate, bladder and colon. In prostate and colon tumours, we find miRNAs over-represented in regions with copy number gain and under-represented in regions with copy number loss. Surprisingly this pattern appears to be reversed in bladder cancer. We compared our miRNA copy number data to published miRNA expression data; unexpectedly, we did not find a statistically significant relationship between miRNA copy number and expression level. This suggests that miRNA expression is regulated through different mechanisms than mRNA expression.
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Viruses represent one of the main factors that cause normal cells to proliferate and to become malignant: up to 15% of all human cancers are associated with single or multiple virus infections, and several viruses have been recognized as causal agents of specific types of cancer. Viruses have evolved many strategies to prevent infected cells from becoming apoptotic and to evade the innate and adaptive immune responses of their hosts. The recent discovery that Epstein-Barr virus and other herpesviruses produce their own sets of micro (mi)RNAs brings an additional layer of complexity in this ongoing host-virus arms race and changes our initial views of the antiviral roles of RNA silencing in plants and insects. It seems that, rather than being inhibited by this process, many mammalian viruses can usurp or divert the host RNA silencing machinery to their advantage. Viral-encoded miRNAs can act both in cis, to ensure accurate expression of viral genomes, and in trans, to modify the expression of host transcripts. Here, we review the current knowledge on viral miRNAs and discuss how mammalian viruses can also perturb host miRNA expression. Those recent findings provide new insights into the role of viruses and miRNAs in cancer development.
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Little is known about the expression levels or function of micro-RNAs (miRNAs) in normal and neoplastic cells, although it is becoming clear that miRNAs play important roles in the regulation of gene expression during development [Ambros, V. (2003) Cell 113, 673-676; McManus, M. T. (2003) Semin. Cancer Biol. 13, 253-258]. We now report the genomewide expression profiling of miRNAs in human B cell chronic lymphocytic leukemia (CLL) by using a microarray containing hundreds of human precursor and mature miRNA oligonucleotide probes. This approach allowed us to identify significant differences in miRNome expression between CLL samples and normal CD5+ B cells; data were confirmed by Northern blot analyses and real-time RT-PCR. At least two distinct clusters of CLL samples can be identified that were associated with the presence or absence of Zap-70 expression, a predictor of early disease progression. Two miRNA signatures were associated with the presence or absence of mutations in the expressed Ig variableregion genes or with deletions at 13q14, respectively. These data suggest that miRNA expression patterns have relevance to the biological and clinical behavior of this leukemia.
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