Colorectal Cancer: From the Genetic Model to Posttranscriptional Regulation by Noncoding RNAs

Figure 3

Biogenesis of miRNAs and translational repression exerted by miRNAs and siRNAs. The nascent pri-miRNA transcripts are first processed into ~70-nucleotide pre-miRNAs by Drosha/DGR8 complexes inside the nucleus. MiRNAs can also be byproducts of mRNA splicing after lariat debranching and 3′-trimming by the exosome complex PM/Scl (mirtrons). Pre-miRNAs (or mitrons) are transported to the cytoplasm by exportin 5 coupled with Ran-GTP and are processed into miRNA:miRNA duplexes by Dicer/TRBP. Dicer also processes endogenous or exogenous dsRNA duplexes. Only one strand of the miRNA:miRNA duplex or the siRNA duplex is preferentially assembled into RISC by the RISC loading complex (RLC). Subsequently, the RISC complex acts on its mRNA target by translational repression or mRNA cleavage, depending, at least in part, on the level of complementarity between the small RNA and its target. Alterations of miRNA function in cancer are multifactorial. They can arise from epigenetic silencing of miRNA genes or may be due to genetic instability as human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers [7, 8]. Dysregulation of miRNA biogenesis machinery is also frequent in cancer mainly due to mutations in one or several of the proteins involved in processing (Drosha, DGCR8, DICER, TRBP, and Argonaute), or in nuclear export (exportin 5), or by alterations in their posttranslational modifications (PTMs) [7, 9–14]. Although specific miRNAs have been described as acting as oncogenes and tumor suppressors, the miRNA expression profile of human tumors is characterized by a general defect in miRNA production that results in global miRNA downregulation. In addition, miRNA sequestration by the so-called miRNA sponges (i.e., circRNAs and lncRNAs) can also contribute to dysregulation of miRNA function. ORF, open reading frame.