MicroRNAs: critical mediators of differentiation, development and disease

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that are expressed in higher eukaryoates and have even been found in viral genomes. They usually act as endogenous repressors of target genes by either inhibiting translation, causing mRNA degradation, or by a combination of both mechanisms. More than 850 mature miRNA sequences have been identified in humans, and although this accounts for less than 2% of human genes, it is predicted that 30% of mRNAs are targeted by miRNAs. miRNAs play critical roles in most cellular processes including development, differentiation, and the homeostasis of both a cell and an organism. Moreover, many disease states, including cancer, occur or are sustained by miRNA dysregulation. In this article, the latest reports of miRNA involvement and aberrant expression in human disease are reviewed, with an emphasis on cancer.

Figure 1

Genomic locations of miRNAs. miRNAs may be located in almost any region of the genome including repeats. They may be grouped into clusters or situated alone, and may be exonic or intronic. A, a miRNA may be part of the exon of a non-coding RNA transcript, such as miR-22. B, polycistronic miRNAs may be grouped into a cluster and transcribed as a pri-miRNA, which yields several miRNAs. This occurs with the miR-100/let-7a-2/miR-125b-1 cluster, which is transcribed as an intron of a non-coding RNA. C, miRNAs may be located in the introns of canonical genes. The mature miRNA may be processed from the intron of the host gene transcript. This occurs when miR-126 is processed from the EGFL7 transcript. Arrow, transcription start site; hairpin, pre-miRNA; rectangle, exon.

Figure 2

The function of tumor suppressor miRNAs. A, normally, a tumor suppressor miRNA is transcribed in the nucleus as a pri-miRNA, processed by Drosha/DGCR8 to a pre-miRNA, exported to the cytoplasm by Exportin-5/RanGTP, processed by Dicer and incorporated into RISC, which mediates translational repression and/or mRNA degradation of the target oncogene. B, decreased levels of a tumor suppressor miRNA, whether by genomic loss or epigenetic silencing as shown (processing defects and transcriptional blocks via trans acting factors may also occur), de-represses the target oncogene, leading to aberrant oncogene translation and tumorigenesis. In the case of miR-101, genomic loss decreases miR-101, causing an increase in its target EZH2, which promotes tumorigenesis.