Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers

Abstract

A large number of tiny noncoding RNAs have been cloned and named microRNAs (miRs). Recently, we have reported that miR-15a and miR-16a, located at 13q14, are frequently deleted and/or down-regulated in patients with B cell chronic lymphocytic leukemia, a disorder characterized by increased survival. To further investigate the possible involvement of miRs in human cancers on a genome-wide basis, we have mapped 186 miRs and compared their location to the location of previous reported nonrandom genetic alterations. Here, we show that miR genes are frequently located at fragile sites, as well as in minimal regions of loss of heterozygosity, minimal regions of amplification (minimal amplicons), or common breakpoint regions. Overall, 98 of 186 (52.5%) of miR genes are in cancer-associated genomic regions or in fragile sites. Moreover, by Northern blotting, we have shown that several miRs located in deleted regions have low levels of expression in cancer samples. These data provide a catalog of miR genes that may have roles in cancer and argue that the full complement of miRs in a genome may be extensively involved in cancers.

Fig. 1.

Correlation between FRAs and miRs. A karyotype showing the position of 113 FRAs and 186 miRs is presented. The 61 miRs located in the same chromosomal band as the FRA are red. We were able to precisely locate 35 miRs inside 12 cloned FRAs. The red arrow shows frequently observed FRAs.

Fig. 2.

Expression of miR-16a, miR-26a, and miR-99a in human tumors and cell lines. (a) Northern blot with B-CLL samples. (b) Northern blot with lung cancer cell lines. The genomic location and the type of alteration are presented.

Fig. 3.

MiRs as cancer players. Some of these proposed mechanisms are experimentally proven, like the HD of miR-15a/miR-16a cluster in B-CLL (9), the c-myc overexpression by the reposition near a putative miR promoter, or miR143/miR-145 cluster down-regulation in colon cancers (39).

Fig. 4.

MiR location and the HOX gene clusters. Drosophila, mouse, and human clusters are presented (for details see text). Each cluster is ≈100 kb; the figure is not drawn to scale.