Circular RNAs: Promising Biomarkers for Human Diseases

Abstract

Circular RNA (circRNA) is a group of endogenous noncoding RNA characterized by a covalently closed cyclic structure lacking poly-adenylated tails. Recent studies have suggested that circRNAs play a crucial role in regulating gene expression by acting as a microRNA sponge, RNA binding protein sponge and translational regulator. CircRNAs have become a research hotspot because of their close association with the development of diseases. Some circRNAs are reportedly expressed in a tissue- and development stage-specific manner. Furthermore, due to other features of circRNAs including stability, conservation and high abundance in body fluids, circRNAs are believed to be potential biomarkers for various diseases. In the present review, we provide the current understanding of biogenesis and gene regulatory mechanisms of circRNAs, summarize the recent studies on circRNAs as potential diagnostic and prognostic biomarkers, and highlight the major advantages and limitations of circRNAs as novel biomarkers based on existing knowledge.

Keywords: Biomarker; Circular RNA; Diseases; Liquid biopsy.

Fig. 1

Possible models of circular RNA biogenesis. (a) Lariat-driven circularization: Exon skipping event results in covalently splices from 3′ splice donor to 5′ splice acceptor, which forms a lariat structure containing the exon 2 and 3 and a linear product of exon 1 and 4. The introns are removed by splicesome to form an ecircRNA (exonic circRNA). (b) Intron-pairing-driven circularization: Direct base-paring of the complementary sequence motifs (such as Alu elements) forms a circulation structure and a linear product. The introns are removed or retained to form an ecircRNA or an EIciRNA (exon-intron circRNA). (c) Circular intronic RNA (ciRNA): The intron lariat is generated from splicing reaction. GU-rich element near the 5′ splice site (orange box) and C-rich element near the branch point (blue box) makes it stable to escape debranching. (d) RNA binding proteins (RBPs)-driven circularization: The interaction between two RBPs can bridge two flanking introns together and form a circRNA and a linear product.

Fig. 2

Putative mechanisms of gene regulation by circular RNAs. (a) CircRNA can act as microRNA (miRNA) sponge which prevents miRNA from interacting with their target messenger (m)RNAs at 3′-untranslated region (UTR). (b) CircRNA can bind to RNA binding proteins (RBPs) that regulate mRNA processing and hence alter the splicing pattern or mRNA stability. (c) CircRNA can regulate the transcription of their parental gene. CiRNA can interact with RNA polymerase II (Pol II) and modulates transcription; EIciRNA (exon-intron circRNA) can interact with U1 small nuclear ribonucleoproteins (snRNPs) and then binds to Pol II. (d) CircRNA can be translated with ribosome and encode proteins.

Fig. 3

Potential application of circular RNAs as liquid biopsy biomarkers. CircRNA biomarkers can be isolated from liquid clinical samples including blood, cerebrospinal fluid, saliva and urine; as well as from the circulating cells and extracellular vesicles contained in these body fluids. Analytical results are used for early diagnosis, therapy selection, prognosis and therapy monitoring of different type of diseases.