Noncoding RNA in oncogenesis: a new era of identifying key players

Abstract

New discoveries and accelerating progresses in the field of noncoding RNAs (ncRNAs) continuously challenges our deep-rooted doctrines in biology and sometimes our imagination. A growing body of evidence indicates that ncRNAs are important players in oncogenesis. While a stunning list of ncRNAs has been discovered, only a small portion of them has been examined for their biological activities and very few have been characterized for the molecular mechanisms of their action. To date, ncRNAs have been shown to regulate a wide range of biological processes, including chromatin remodeling, gene transcription, mRNA translation and protein function. Dysregulation of ncRNAs contributes to the pathogenesis of a variety of cancers and aberrant ncRNA expression has a high potential to be prognostic in some cancers. Thus, a new cancer research era has begun to identify novel key players of ncRNAs in oncogenesis. In this review, we will first discuss the function and regulation of miRNAs, especially focusing on the interplay between miRNAs and several key cancer genes, including p53, PTEN and c-Myc. We will then summarize the research of long ncRNAs (lncRNAs) in cancers. In this part, we will discuss the lncRNAs in four categories based on their activities, including regulating gene expression, acting as miRNA decoys, mediating mRNA translation, and modulating protein activities. At the end, we will also discuss recently unraveled activities of circular RNAs (circRNAs).

Figure 1

MicroRNA biogenesis and their role in inhibiting gene expression. A miRNA is transcribed by RNA polymerase II (Pol II) mediated by other transcription factors, such as p53 and c-Myc. The generated pri-miRNA is processed by the DROSHA complex to become a pre-miRNA, which is transported from nucleus to cytoplasm with a complex consisting of Exportin-5 (Exp-5) and Ran-GTP. In cytoplasm, the pre-miRNA is further processed by a Dicer-1 complex to become a duplex that consists of a guide strand (to become a mature miRNA) and a passenger strand. The guide strand associates with the RNA-induced silencing complex (RISC) and guides it to the target site on the 3′-UTR of an mRNA to inhibit the mRNA translation and cause mRNA degradation. For some miRNA-duplexes post Dicer-1 processing, both strands can become mature miRNAs; the one at the 5′-end of pre-miRNA is suffixed by “-5p”, while the 3′-end one is suffixed by “-3”, such as miR-17-5p and miR-17-3p.

Figure 2

The interplay between miRNAs and p53. While p53 regulates the gene expression of many miRNAs, its expression is also inhibited by miRNAs. When cells are exposed to genotoxic stresses, p53 activates four miRNAs that repress Mdm2 expression, which leads to p53 accumulation and cell cycle arrest or apoptosis. P53 protein also associates with the DROSHA complex to directly regulate miRNA maturation.

Figure 3

The interplay between miRNAs and c-Myc. While c-Myc regulates the expression of multiple miRNAs, its expression is inhibited by different miRNAs. C-Myc also activates the gene expression of DROSHA to directly promote miRNA procession.

Figure 4

PTEN expression is regulated by multiple ncRNAs. (A) The PTEN pseudogene, PTENP1, can transcribe into the PTENP1 lncRNA that acts as a decoy to sponge the miRNAs targeting at the 3′-UTR of the PTEN mRNA; (B,C) The locus of the PTEN pseudogene can also transcribe from the reverse direction to make two antisense RNA (asRNA) isoforms, α and β; (B) The α asRNA isoform binds the PTEN promoter and recruits DNMT3A, EZH2 and G9A, which causes epigenetic silencing of the PTEN gene; (C) The β asRNA isoform associates with the PTENP1 lncRNA to increase its stability and miRNA decoy activity; (D) The ZEB2 mRNA has a long 3′-UTR with many binding sites of miRNAs that also potentially target the PTEN 3′-UTR. Thus, the ZEB2 mRNA acts as a decoy to sponge many miRNAs and consequently promotes PTEN expression.