The Role of circRNAs in Human Papillomavirus (HPV)-Associated Cancers

Abstract

Circular RNAs (circRNAs) are a new class of "non-coding RNAs" that originate from non-sequential back-splicing of exons and/or introns of precursor messenger RNAs (pre-mRNAs). These molecules are generally produced at low levels in a cell-type-specific manner in mammalian tissues, but due to their circular conformation they are unaffected by the cell mRNA decay machinery. circRNAs can sponge multiple microRNAs or RNA-binding proteins and play a crucial role in the regulation of gene expression and protein translation. Many circRNAs have been shown to be aberrantly expressed in several cancer types, and to sustain specific oncogenic processes. Particularly, in virus-associated malignancies such as human papillomavirus (HPV)-associated anogenital carcinoma and oropharyngeal and oral cancers, circRNAs have been shown to be involved in tumorigenesis and cancer progression, as well as in drug resistance, and some are useful diagnostic and prognostic markers. HPV-derived circRNAs, encompassing the HPV E7 oncogene, have been shown to be expressed and to serve as transcript for synthesis of the E7 oncoprotein, thus reinforcing the virus oncogenic activity in HPV-associated cancers. In this review, we summarize research advances in the biogenesis of cell and viral circRNAs, their features and functions in the pathophysiology of HPV-associated tumors, and their importance as diagnostic, prognostic, and therapeutic targets in anogenital and oropharyngeal and oral cancers.

Keywords: HPV-associated cancers; biomarkers; circRNAs; squamous cell carcinoma.

Figure 1

Classification and biogenesis of circRNAs. (A) Lariat-guided circularization: an exon skipping event leads to a lariat structure that contains exons 2 and 3, formed by the link between the 3′ end of a donor exon with the 5′ end of the acceptor exon, and a linear product consisting of exons 1 and 4. EcircRNA is formed after removal of introns. (B) Circularization is driven by intron-pairing: the pairing of complementary sequences (Alu elements) leads to a circular product and a linear product. Introns are maintained or removed to form an EIciRNA (exon-intron circRNA) or an ecircRNA, respectively. (C) Circular intronic RNA (ciRNA): the splicing reaction generates the intron lariat. An element rich in GU, near the junction site 5′, and an item rich in C, near the branching point, make it stable enough to escape from debranching. (D) Circularization guided by RNA binding proteins (RBP): the interaction between two RBPs joins two flanking introns to form a circRNA and a linear product. (E) tRNA intronic circRNA (tricRNA) originates from pre-tRNA cleaved by the tRNA splicing endonuclease complex.

Figure 2

HPV-associated cancers. Types of cancer caused by HPV. The percentage of cancers caused by HPVs is from the United States data from the National Cancer Institute.