The role of MicroRNAs in human cancer

Abstract

MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that function in regulation of gene expression. Compelling evidences have demonstrated that miRNA expression is dysregulated in human cancer through various mechanisms, including amplification or deletion of miRNA genes, abnormal transcriptional control of miRNAs, dysregulated epigenetic changes and defects in the miRNA biogenesis machinery. MiRNAs may function as either oncogenes or tumor suppressors under certain conditions. The dysregulated miRNAs have been shown to affect the hallmarks of cancer, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, activating invasion and metastasis, and inducing angiogenesis. An increasing number of studies have identified miRNAs as potential biomarkers for human cancer diagnosis, prognosis and therapeutic targets or tools, which needs further investigation and validation. In this review, we focus on how miRNAs regulate the development of human tumors by acting as tumor suppressors or oncogenes.

Figure 1

microRNA biogenesis. miRNA genes are usually transcribed by RNA polymerase II to produce the large primary transcripts termed pri-miRNAs, which are cleaved by a microprocessor complex, composed of RNA-binding protein DGCR8 and type III RNase Drosha, into an ~85-nucleotide stem–loop structure called pre-miRNA. Following transportation by Ran/GTP/Exportin 5 complex from nucleus to cytoplasm, the pre-miRNAs are processed by another RNase III enzyme Dicer to a ~20–22-nucleotide miRNA/miRNA* duplex. After the duplex is unwound, the mature miRNA is incorporated into a protein complex termed RISC. A miRNA-loaded RISC mediates gene silencing via mRNA cleavage and degradation, or translational repression depending on the complementarity between the miRNA and the targeted mRNA transcript. In addition, miRNAs may function as ligands to directly binding with Toll-like receptor (TLR), triggering downstream signaling pathways. Methyltransferase-like 3 (METTL3) is recently discovered to methylate pri-miRNAs, marking them for recognition and processing by DGCR8 to yield mature miRNA.