Causes and consequences of microRNA dysregulation in cancer

Abstract

Over the past several years it has become clear that alterations in the expression of microRNA (miRNA) genes contribute to the pathogenesis of most--if not all--human malignancies. These alterations can be caused by various mechanisms, including deletions, amplifications or mutations involving miRNA loci, epigenetic silencing or the dysregulation of transcription factors that target specific miRNAs. Because malignant cells show dependence on the dysregulated expression of miRNA genes, which in turn control or are controlled by the dysregulation of multiple protein-coding oncogenes or tumour suppressor genes, these small RNAs provide important opportunities for the development of future miRNA-based therapies.

Figure 1. MicroRnA genes map to chromosomal regions that are involved in alterations in human cancer

The 24 human chromosomes are shown, with stars indicating the locations of microRNA-gene-containing regions that are implicated in cancer (one star = one microRNA gene). Many microRNAs map to chromosome regions that are involved in rearrangements in human cancer. For example, miR-15-a and miR-16-1 map to 13q14, a region that is frequently deleted in chronic lymphocytic leukaemia. miR-29a and miR-29b map to 7q32, a region that is deleted in myelodysplastic syndrome and acute myeloid leukaemia. The let-7g–let-7a1 cluster maps to 3p2, the let-7f-1–let-7d cluster maps to 9q22.3, let-7a-2 maps to 11q23-q24 and let-7c maps to 21q21 —all of these regions are involved in deletions in a range of solid malignancies, including lung, urothelial, breast, ovarian and cervical cancers.

Figure 2. Role of miR-106b-25 and miR-17-92 clusters in the control of transforming growth factor β(TGFβ) signaling

This figure shows the genomic organization of the three related microRNA clusters mapping on chromosomes (Chr) 13,7 and X. The homology between the different individual microRNAs is indicated by the same colors. MiR-106b-25/miR-17-92 regulates the Myc/E2F1/TGFβ network. Both MCM7 and c13orf25 microRNA host genes are induced by Myc and E2F1. Elevated expression of microRNAs of the miR-106 family consisting of miR-106b, miR-92, miR-17-5p and miR-20a causes reduced expression of p21, a cell cycle inhibitor, thus inhibiting TGFβ dependent cell cycle arrest. Elevated expression of miR-25/miR-92 affects TGFβ-induced apoptosis through inhibition of Bim expression. Since overexpression of Myc induces apoptosis, possibly through Bim induction, elevated expression of miR-25/92 can avoid Myc induced apoptosis in cancer cells.