Circular RNAs Sparkle in the Diagnosis and Theranostics of Hepatocellular Carcinoma

Abstract

Exonic circular RNAs (circRNAs) are a novel subgroup of non-coding RNAs, which are generated by a back-splicing mechanism of the exons or introns. Unlike the linear RNA, circRNA forms a covalently closed loop, and it normally appears more abundant than the linear products of its host gene. Due to the relatively high specificity and stability of circular RNAs in tissues and body fluid, circular RNAs have attracted widely scientific interest for its potential application in cancer diagnosis and as a guide for preclinical therapy, especially for hard-to-treat cancers with high heterogeneity, such as hepatocellular carcinoma (HCC). Thus, we summarize the updated knowledge of circular RNAs, including the mechanism of the generation of endogenous circular RNAs and their regulatory, diagnostic, and therapeutic roles in HCC.

Keywords: HCC; biomarker; circRNA; hepatocellular carcinoma; therapy.

FIGURE 1

The endogenous biosynthesis of circRNAs. (I) Longflanking introns and inverted repeat elements (such as Alu elements) promote competition between the linear splicing and back-splicing of exons, leading to the generation of EcRNAs. (II) Some RBPs like MBL and QKI can recognize the specific motifs within flanking introns and directly bind on them, dragging two splicing sites close enough to promote back-splicing subsequently. (III) Some RBPs like DHX and ADAR1 disrupt base pairing between inverted repeat elements, allowing the splicing machinery to generate linear mRNA. (IV) TricRNAs are generated from introns spliced from pre-tRNA (V). Intergenic circRNAs contains two intronic circRNA fragments.

FIGURE 2

General biological functions of circRNAs. (I,II) EIciRNAs and ciRNAs function as enhancers of specific proteins by binding with the RNA polymerase II (Pol II) complex. (III) EcircRNAs are generated through back-splicing and translocate from the nucleus into the cytoplasm. (IV) Exonic circRNAs that contain internal ribosome entry sites (IRES) or prokaryotic binding sites translate into peptides. (V) EcircRNAs function as miRNA sponges. (VI) EcircRNAs can act as a decoy or scaffold to sequester proteins and regulate gene expression or functional protein localization.