The role of circRNAs in cancers

Abstract

Circular RNAs (circRNAs) are recently regarded as a naturally forming family of widespread and diverse endogenous noncoding RNAs (ncRNAs) that may regulate gene expression in mammals. At present, above 30000 circRNAs have already been found, with their unique structures to maintain stability more easily than linear RNAs. Several previous literatures stressed on the important role of circRNAs, whose expression was relatively correlated with patients' clinical characteristics and grade, in the carcinogenesis of cancer. CircRNAs are involved in many regulatory bioprocesses of malignance, including cell cycle, tumorigenesis, invasion, metastasis, apoptosis, vascularization, through adsorbing RNA as a sponge, binding to RNA-binding protein (RBP), modulating transcription, or influencing translation. Therefore, it is inevitable to further study the interactions between circRNAs and tumors and to develop novel circRNAs as molecular markers or potential targets, which will provide promising applications in early diagnosis, therapeutic evaluation, prognosis prediction of tumors and even gene therapy for tumors.

Keywords: Biomarker; Cancer; Circular RNAs; Function.

Figure 1. Schematic representation of splicing events and biological functions of circRNAs

(a) Linear mRNA is generated conventionally through canonical splicing machinery. (b) Exonic circRNA is formed through backsplicing of the 5′ splice site (donor site) to a 3′ splice site (acceptor site) which is called head-to-tail joining. (c) Reverse complementary sequences of lariat intron excised from pre-mRNA can pair to produce close loop structure named as ciRNA. (d) The intron2 is then removed and brings the 5′ splice site of Exon3 close to 3′ splice site of Exon2, to form a circRNA, which contains multiple exons. (e) Also, intron3 will be retained, with Exon3 and Exon4, forming an EIciRNA. (f) The stable ciRNA binds to elongating RNA Pol II and promotes transcription. (g) EIciRNAs can enhance gene transcription via interacting with U1 snRNP and RNA polymerase II in the promoter region of the host gene.

Figure 2. The expulsion and transport of circRNAs

(a) Without 5′ caps and 3′ tails, circRNAs which can resist degradat by RNase R, are highly stable. (b,c) Extracellular vesicles can carry a myriad of cellular components, including proteins, lipids, and RNA, despite their small size. Also, extracellular vesicle release may be one of the ways for cells to eliminate circRNAs. (d,e) Exosomes release the endocytosed contents to the external environment or distant target cells, to transfer biological signals through one cell to another.

Figure 3. The biological functions of circRNA

(a) CircRNAs act as miRNA sponge to compete endogenous RNA and sequester miRNAs from binding mRNA targets to influence the protein translation. (b) CircRNAs can also work as RBP sponge to interact with RBPs, forming RNA–protein complex (RPC). (c) The synthetic circRNA which contains an internal ribosome entry site (IRES) can be translated to produce proteins in vitro.