MicroRNA in Cancer: The Involvement of Aberrant MicroRNA Biogenesis Regulatory Pathways

Abstract

MicroRNAs (miRNAs) are small, noncoding RNAs that influence diverse biological outcomes through the repression of target genes during normal development and pathological responses. In particular, the alteration of miRNA expression has dramatic consequences for the progression of tumorigenesis. miRNAs undergo two processing steps that transform a long primary transcript into the mature miRNA. Although the general miRNA biogenesis pathway is well established, it is clear that not all miRNAs are created equally. Recent studies show that miRNA expression is controlled by diverse mechanisms in response to cellular stimuli. In this review, we discuss the mechanisms that govern the regulation of miRNA biogenesis with particular focus on how these mechanisms are perturbed in cancer.

Keywords: Dicer; Drosha; biogenesis; cancer; microRNA.

Figure 1.

General mechanism of miRNA biogenesis. miRNAs are initially transcribed as a long, capped, and polyadenylated pri-miRNA. The Drosha complex crops the pri-miRNA into a hairpin-shaped pre-miRNA. Next, Exportin-5 promotes the nuclear translocation of the pre-miRNA, which is further processed by the Dicer complex. Following Dicing, the resulting miRNA:miRNA* is dissociated, and the mature miRNA is incorporated into the RISC, where it functions to mediate gene silencing either by translational inhibition or by promoting the degradation of target mRNAs.

Figure 2.

p68/p72-dependent miRNA processing pathways. The RNA helicases p68 and p72 play a critical role in the posttranscriptional regulation of numerous miRNAs in response to cellular signals, including TGF-β stimulation, DNA damage, and estrogen stimulation. The downstream mediators of TGF-β stimulation and DNA damage, the Smads and p53, act to promote miRNA processing. Conversely, when bound to E2, ER-α reduces the processing of a subset of miRNAs. The bottom column indicates miRNAs known to be posttranscriptionally regulated by each pathway. For clarity, DGCR8 and other potential members of the Drosha processing complex are not shown.

Figure 3.

RNA helicase-independent mechanisms of miRNA processing regulation. (A) hnRNP A1 recognizes the terminal loop of a subset of miRNAs and promotes the structural remodeling of the stem region. Structural rearrangement creates a more favorable Drosha binding site and enhances pri- to pre-miRNA processing. (B) KSRP binds to the loop region of a subset of miRNAs and promotes both the Drosha and Dicer processing. (C) Several mechanisms of Lin28-regulated miRNA processing have been reported. Lin28 prevents the association of both Drosha and Dicer with the pri- and pre-miRNAs, respectively. Additionally, Lin28 acts as a scaffold to promote the association of TUT4 with the pre-miRNA. TUT4 promotes the 3′ uridinylation of pre-miRNA, which is then rapidly degraded. Together, these mechanisms allow the tight control of let-7 expression by Lin28. (D) NF90 and NF40 strongly associate with the double-stranded stem region of pri-miRNAs. This association precludes association with the Drosha processing complex and thus inhibits the processing of a subset of miRNAs.