The Three Paralogous MicroRNA Clusters in Development and Disease, miR-17-92, miR-106a-363, and miR-106b-25

Abstract

MicroRNAs (miRNAs) form a class of noncoding RNA genes whose products are small single-stranded RNAs that are involved in the regulation of translation and degradation of mRNAs. There is a fine balance between deregulation of normal developmental programs and tumor genesis. An increasing body of evidence suggests that altered expression of miRNAs is entailed in the pathogenesis of human cancers. Studies in mouse and human cells have identified the miR-17-92 cluster as a potential oncogene. The miR-17-92 cluster is often amplified or overexpressed in human cancers and has recently emerged as the prototypical oncogenic polycistron miRNA. The functional analysis of miR-17-92 is intricate by the existence of two paralogues: miR-106a-363 and miR-106b-25. During early evolution of vertebrates, it is likely that the three clusters commenced via a series of duplication and deletion occurrences. As miR-106a-363 and miR-106b-25 contain miRNAs that are very similar, and in some cases identical, to those encoded by miR-17-92, it is feasible that they regulate a similar set of genes and have overlapping functions. Further understanding of these three clusters and their functions will increase our knowledge about cancer progression. The present review discusses the characteristics and functions of these three miRNA clusters.

Figure 1

Biogenesis and mechanism of action of miRNAs. (a) miRNAs are transcribed mainly by polymerase II (A) from a gene encoding a single miRNA (B), or from a polycistronic gene (C), or from a gene in an intronic region (D). Resulting pri-miRNAs are processed by type III RNase Drosha. The newly formed stem-loop structure, pre-miRNA, is recognized by the XPO5, RanGTP complex, and is transported to the cytoplasm by exportin-5 (E). Dicer cleaves the loop (F), leaving a double-stranded fragment, the miRNA-3p:miRNA-5p duplex (G). The duplex is then unwound and loaded into the miRISC complex (H) where it recognizes and anneals to the UTR of mRNA target (I). The messenger RNA:miRISC complex mediates translational repression (J) or mRNA decay (K). (b) Processing of a pre-miRNA gives rise to two mature miRNAs named miR-XXX-3p and miR-XXX-5p where miR-XXX-3p miRNA originates from 3′-end and miR-XXX-5p miRNA originates from 5′-end of the pre-miRNA.

Figure 2

Schematic illustration of possible regulatory interactions between miRNAs encoded by the three paralogue clusters and with the E2F transcription factor family. Stimulatory effects are shown using green lines; inhibitory effects are shown using red lines.