Regulatory Mechanism of MicroRNA Expression in Cancer

Abstract

Altered gene expression is the primary molecular mechanism responsible for the pathological processes of human diseases, including cancer. MicroRNAs (miRNAs) are virtually involved at the post-transcriptional level and bind to 3' UTR of their target messenger RNA (mRNA) to suppress expression. Dysfunction of miRNAs disturbs expression of oncogenic or tumor-suppressive target genes, which is implicated in cancer pathogenesis. As such, a large number of miRNAs have been found to be downregulated or upregulated in human cancers and to function as oncomiRs or oncosuppressor miRs. Notably, the molecular mechanism underlying the dysregulation of miRNA expression in cancer has been recently uncovered. The genetic deletion or amplification and epigenetic methylation of miRNA genomic loci and the transcription factor-mediated regulation of primary miRNA often alter the landscape of miRNA expression in cancer. Dysregulation of the multiple processing steps in mature miRNA biogenesis can also cause alterations in miRNA expression in cancer. Detailed knowledge of the regulatory mechanism of miRNAs in cancer is essential for understanding its physiological role and the implications of cancer-associated dysfunction and dysregulation. In this review, we elucidate how miRNA expression is deregulated in cancer, paying particular attention to the cancer-associated transcriptional and post-transcriptional factors that execute miRNA programs.

Keywords: cancer; epigenetic modification; genetic alterations; microRNA; microRNA biogenesis; post-transcriptional regulation.

Figure 1

Schematic illustration of miRNA biogenesis dysregulation in cancer. The nascent primary miRNA (pri-miRNA) is transcribed by RNA Polymerase II (Pol II). The pri-miRNA is initially cleaved by DROSHA/DGCR8 microprocessor complex in the nucleus, which releases a hairpin shaped precursor (pre-miRNA). Pre-miRNA is then exported from the nucleus to the cytoplasm by exportin 5 (XPO5). In the cytoplasm, DICER1 cleaves pre-miRNA to produce the miRNA duplex, which is loaded onto the Argonaute (AGO) protein. AGO preferentially retains one strand mature miRNA and further associates with other cofactors including GW182, forming the effector complex called RNA-induced silencing complex (RISC). The RISC induces the translational suppression and mRNA degradation through the interaction with the complementary sequences in the 3’-untranslated region (3’-UTR) of target mRNA.