Circular RNAs in Cancer: emerging functions in hallmarks, stemness, resistance and roles as potential biomarkers

Abstract

Circular RNAs (circRNAs) are a class of RNA molecules with closed loops and high stability. CircRNAs are abundantly expressed in eukaryotic organisms and exhibit both location- and step-specificity. In recent years, circRNAs are attracting considerable research attention attributed to their possible contributions to gene regulation through a variety of actions, including sponging microRNAs, interacting with RNA-binding proteins, regulating transcription and splicing, and protein translation. Growing evidence has revealed that circRNAs play critical roles in the development and progression of diseases, especially in cancers. Without doubt, expanding our understanding of circRNAs will enrich knowledge of cancer and provide new opportunities for cancer therapy. In this review, we provide an overview of the characteristics, functions and functional mechanisms of circRNAs. In particular, we summarize current knowledge regarding the functions of circRNAs in the hallmarks, stemness, resistance of cancer, as well as the possibility of circRNAs as biomarkers in cancer.

Keywords: Biomarker; Cancer; CircRNAs; Function; Hallmarks; Resistance; Stemness.

Fig. 1

Formation of three types of circRNAs. a Exonic circular RNA (ecircRNA) is formed through back-splicing of the 5’splice site (splice donor site) to a 3’splice site (splice acceptor site); (b) The intron 1 is removed and bring the 5′ splice site of Exon 2 close to 3′ splice site of Exon 1, to form a ecircRNA that contains multiple exons. Exons can also skip splicing, exon 1 can also link with exon 3; (c) Circular intronic RNA (ciRNA) are derived from intron lariats that escape the normal intron debranching and degradation. Reverse complementary sequences of lariat intron excised from pre-mRNA can pair to produce close loop structure termed as ciRNA; (d) Exon–intron circRNAs (EIciRNAs) are circularized with introns‘retained’between the exons. Intron 3 retaines with Exon 3 and Exon 4 to form an EIciRNAs

Fig. 2

The functional mechanisms of CircRNAs. a Acting as miRNA sponge; (b) Binding with RNA binding protein (RBP); (c) Regulating transcription; (d) Regulating splicing; (e) Translated into Protein; (f) Regulating epigenetic alterations

Fig. 3

CircRNAs involved in the hallmarks of cancer. a CDR1as and circHIPK3 active cell proliferative through regulating EGFR; (b) Circ-ITCH et al. promote cancer cells evading antigrowth signals by preventing expression or activation of tumor suppressors, such as PTEN and CDK; (c) Hsa_circ_0007534 et al. promote cancer cells evading cell death via regulating cellular apoptosis or autophagy; (d) Has-circ-0020397 limits replicative potential of cancer cell trough regulating TERT; (e) CircRNA-MYLK et al. sustain angiogenesis trough regulating VEGF; (f) Dirc-10,720 et al. regulate the process of EMT and thus tissue invasion and metastasis of cancer