Review
MicroRNAs and genomic instability

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Abstract

A new species of non-coding RNA, microRNAs (miRNAs) has been identified that may regulate the expression of as many as one third to one half of all protein encoding genes. MicroRNAs are found throughout mammalian genomes, but an association between the location of these miRNAs and regions of genomic instability (or fragile sites) in humans has been suggested [1]. In this review we discuss the possible role of altered miRNA expression on human cancer and conduct an analysis correlating the physical location of murine miRNAs with sites of genetic alteration in mouse models of cancer.

Introduction

Regions of genomic instability can reflect alterations that result in loss, gain, or altered gene expression depending on the nature of the underlying genetic lesion and the function of the gene(s) affected. A critical marker of genomic instability is the presence of chromosomal translocations, and the analysis of breakpoint regions surrounding such genomic rearrangements has lead to discovery of some of the most important genes in cell biology. For example, the original experiments of Nowell and Hungerford [2] connected the Philadelphia chromosome (Ph′), generated by a T(9:22) translocation with chronic myelogenous leukemia (CML) and subsequent molecular analysis of the breakpoints showed that this results in the formation of the BCR-ABL fusion oncogene [3]. Similar cytogenetic studies in Burkitt's Lymphoma identified T(8:14) as a major chromosomal translocation event [4], [5]. Follow up molecular studies showed that as a result of this translocation the proto-oncogene c-MYC is placed adjacent to the immunoglogulin heavy chain gene leading to cell transformation [6]. In contrast to the pattern of chromosomal translocation with oncogenes, it was the loss of heterozygosity (LOH) at the 13q14 locus as reported by Cavenee and colleagues in 1983 that provided the first molecular evidence of a tumor suppressor locus [7] and identification of the retinoblastoma (RB) gene. More recently, Calin and co-workers have reported that subsets of the newly identified species of non-coding RNAs (ncRNAs) called microRNAs (miRNAs), are clustered in regions of genomic instability or fragile sites [1], [8]. With at least several hundred miRNAs found throughout the genome and estimates that miRNAs can regulate the expression of at least 30% of protein encoding genes [9], [10], [11] not only the location but also the function of these miRNAs could play a significant role in the characterization of normal and tumor cells.

Section snippets

MicroRNA biogenesis and function

MicroRNAs are first transcribed in the nucleus as primary transcripts some of which can be very large and include polycistronic transcripts encoding multiple miRNAs. Primary miRNA transcripts are transcribed by RNA polymerase II using either independent promoters or, as some are found in the introns of protein-encoded genes, they may use the promoter of the proximal coding gene [12], [13], [14]. A critical feature of microRNA biogenesis is the formation of a precursor miRNA hairpin structure of

MicroRNAs and cancer

One of the first reports on an association between miRNAs and human cancer involved the miRNAs hsa-miR-15a and hsa-miR-16-1 which were found to be down regulated or deleted in 70% of tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL). As these miRNAs map to a region of minimal deletion (30 kb) that is associated with LOH (13q14) in B-CLL, a role for these particular miRNAs in oncogenesis has been proposed [8], [52]. Interestingly, a predicted target of both hsa-miR-15a

MicroRNA clusters in the human genome

Many clusters of miRNAs have been identified within the human genome. Some clusters reflect the processing of a number of miRNAs from a single large polycistronic transcript such that presumably all of the miRNAs are under the same promoter and in the same transcriptional orientation. Other clusters of miRNA genes may simply reflect close physical location but independent transcriptional regulation (either same or opposite transcriptional orientation). In terms of distance, clustering on longer

Mouse miRNAs and genomic location

The relationship between the location of miRNAs at or near sites of genomic instability has been examined mainly using human data, however, mouse models of cancer are an abundant source of chromosomal breakpoint information primarily from the use of murine retroviruses (e.g. Moloney Murine leukemia virus, Mo-MuLV) and the diseases caused by integration of these constructs. We thus compared the position of the annotated mouse miRNAs reported within the Sanger miRNA registry (//microrna.sanger.ac.uk/

Conclusion

In this analysis, we have focused on clusters of mouse miRNAs found in close proximity to known sites of retroviral integration and/or genomic instability assuming such clusters may exhibit altered expression as a consequence of genomic rearrangement. Given the potential for individual miRNAs to regulate multiple gene targets, a change in the expression of a single miRNA, let alone the aberrant expression of a miRNA cluster, could have significant consequences. Moreover, although not discussed

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      Citation Excerpt :

      The multistage oncogene-mutation and clonal proliferation (MPP) theory of carcinogenesis (Fig. 1), first proposed by Armitage and Doll in 1957 [2], is the most general, overlapping nearly all of the other theories, because the critical events it posits (oncogene mutation and/or premalignant-cell proliferation) can be induced or augmented by events highlighted by those other theories (including oxidative stress, infection, inflammation, wound healing, chromosome damage, and genomic instability). Likewise, wound healing and response to chronic infection typically involve inflammation and its characteristic microenvironment [52,53,63,64,68], which in turn may be associated with aberrant DNA methylation patterns [60,62,82,85], which in turn can activate patterns of (e.g., oncogenic) microRNA expression [83,84,86], which in turn characteristically arise within inflammation microenvironments [66], induce genomic instability [137], or directly affect and/or mediate oncogene expression [110,117,120,126]. While all seven theories focus on events required for generating malignant tumors, most posit or imply that benign tumors have incurred a only subset of events required for, and thus typically represent an early or intermediate stage of, complete malignant progression (Fig. 1, [78,85]).

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