Circular RNAs and their roles in head and neck cancers

Abstract

Circular RNAs are abundant endogenous non-coding RNA with no 5' cap and 3' polyadenylation tail that modify liner mRNAs and have no terminal structures. Our knowledge of the biogenesis of circular RNAs has been expanded, and circular RNAs were shown to be key regulators of various diseases, especially cancers. Head and neck cancers are the sixth most popular cancers worldwide, and the overall survival rates remain unsatisfactory. Recent studies have indicated that circular RNAs are involved in the tumorigenesis, progression, invasion and chemosensitivity of head and neck cancers and that some circular RNAs could serve as diagnostic and prognostic biomarkers. In this study, we summarize research advances in the regulation of circular RNA biogenesis, their characteristics and functions, the involvement of circular RNAs in the pathophysiology of head and neck cancers and their potential clinical utilization, as well as the likely directions of future studies.

Keywords: Biogenesis; Biomarker; Characteristics; Circular RNA; Head and neck cancer; Sponge function.

Fig. 1

The formation and classification of circRNAs. Canonical splicing produces liner mRNAs (a) while back-splicing generates circRNAs (b). b. CircRNAs were usually categorized into ecircRNAs, ciRNAs and EIciRNAs depending on their components, which were derived from exons and introns, and both of them in pre-mRNAs, respectively. Different ecircRNAs could be generated from one pre-mRNA via alternative splicing. The red segment and yellow segment between Exon 4 and Exon 5 represented a 7-nt GU-rich motif near the 5′ splice site and an 11-nt C-rich motif at the branchpoint site, respectively, which promoted the generation of ciRNAs

Fig. 2

Three models for the biogenesis of ecircRNAs. a. Lariat-driven circularization, also known as the exon-skipping model. The remaining exons in the pre-mRNAs were allocated into the concomitant linear mRNAs. b. Intronic base pairing-driven circularization. The pairing across complement sequences in the flanking introns brought the splicing sites into proximity, facilitating the circularization of intervening exons. c. RBP-driven circularization. The interactions of RBPs binding to the flanking introns serve as a bridge to bring the introns into proximity, promoting the process of circularization. d, e. Some RBPs could bind to the intronic dsRNA to regulate the biogenesis of ecircRNAs. While some RBPs (such as NF90/NF110) stabilize the dsRNAs to promote the generation of ecircRNAs (d), some RBPs (such as DHX9 and ADAR1) destroy the stability of dsRNAs to suppress the generation of ecircRNAs (e)