Review on circular RNAs and new insights into their roles in cancer

Abstract

Circular RNAs (circRNAs) are a very interesting class of conserved single-stranded RNA molecules derived from exonic or intronic sequences by precursor mRNA back-splicing. Unlike canonical linear RNAs, circRNAs form covalently closed, continuous stable loops without a 5'end cap and 3'end poly(A) tail, and therefore are resistant to exonuclease digestion. The majority of circRNAs are highly abundant, and conserved across different species with a tissue or developmental-stage-specific expression. circRNAs have been shown to play important roles as microRNA sponges, regulators of gene splicing and transcription, RNA-binding protein sponges and protein/peptide translators. Emerging evidence reveals that circRNAs function in various human diseases, particularly cancers, and may function as better predictive biomarkers and therapeutic targets for cancer treatment. In consideration of their potential clinical relevance, circRNAs have become a new research hotspot in the field of tumor pathology. In the present study, the current understanding of the biogenesis, characteristics, databases, research methods, biological functions subcellular distribution, epigenetic regulation, extracellular transport and degradation of circRNAs was discussed. In particular, the multiple databases and methods involved in circRNA research were first summarized, and the recent advances in determining the potential roles of circRNAs in tumor growth, migration and invasion, which render circRNAs better predictive biomarkers, were described. Furthermore, future perspectives for the clinical application of circRNAs in the management of patients with cancer were proposed, which could provide new insights into circRNAs in the future.

Keywords: AML, acute myloid leukemia; BSJ, back-splice junction; Biomarker; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CRC, colorectal cancer; Cancer; Circular RNAs; EIciRNAs, exon–intron RNAs; EMT, epithelial-mesenchymal transition; Functions; GC, gastric cancer; HCC, hepatocellular carcinoma; ISH, in situ hybridization; LUAD, lung adenocarcinoma; MER, miRNA response elements; MM, multiple myeloma; NSCLC, non-small cell lung cancer; PCR, polymerase chain reaction; PDAC, pancreatic ductal adenocarcinoma; RBP, RNA-binding protein; RNA, ribonucleic acid; RNase, ribonuclease; RT-PCR, reverse transcription-PCR; TNM, tumor node metastases; UTR, untranslated regions; ccRCC, clear cell renal cell carcinoma; ceRNAs, endogenous RNAs; ciRNAs, circular intronic RNAs; ciRS-7, circular RNA sponge for miR-7; circRNAs, circular RNAs; ecircRNAs, exonic circular RNAs; lncRNAs, long ncRNA; miRNAs, microRNAs; ncRNAs, noncoding RNAs; qPCR, quantitative PCR; rRNA, ribosomal RNA; siRNAs, small interfering RNAs; snRNA, small nuclear RNA; tricRNAs, tRNA intronic circRNAs.

Graphical abstract

Fig. 1

Biogenesis, functions and degradation of circRNA. (A) Biogenesis of circRNAs. (a) circRNA formation through RBP-mediated pre-miRNA folding. (b) Pairing between the 2 introns flanking the circularized exons. (c) The back-splicing site promotes the joining of the downstream 5’donor sites with the upstream 3’acceptor sites. (d) tricRNA exon termini link to each other to form a mature tRNA, and intron termini are ligated together to form tricRNA. (B) Functions and degradation of circRNAs. circRNAs could (1) bind RBPs as transcription regulators, (2) function as miRNA sponges, (3) be translated into proteins/peptides, (4) generate pseudogenes, (5) sponge miRNA for direct degradation and (6) be degraded by endonucleases. (7) The circRNA-complex may diffuse in the cytoplasm or be actively transported into particular regions of the cell (e.g., the synapse) where it can release its bound cargo or start to be translated. (8) The enclosure of circRNAs or circRNA factor complexes in vesicles could be released into the extracellular space, which would remove circRNAs from the cytoplasm. (9) The circRNA or circRNA complexes could reach other cells or tissues and therefore act as messenger molecules or fulfill other unknown functions.

Fig. 2

Overview of functional circRNAs in various types of cancer. The map shows the circRNAs that have been confirmed to function in various types of cancer.

Fig. 3

Strategies of circRNA research (identification, validation, function and mechanism).