According to the human genomic data, approximately 75% of genes are transcribed into RNAs, of which more than 20,000 are protein-coding genes. About 2% of the total genomic sequences can be translated into proteins for multiple biological functions (1-3). Non-coding RNA (ncRNA), known as the major component of human transcriptome, participates in the pathological processes of various diseases by interfering directly or indirectly with target gene expression (4-7). In addition to the well-known classical ncRNA such as transfer RNA (tRNA) and ribosomal RNA (rRNA), ncRNA also includes long non-coding RNA (lncRNA, ≥200 nucleotides) and small non-coding RNA (sncRNA, ≤200 nucleotides), according to the length of RNA (8).
Another type of ncRNA, circular RNA (circRNA), is novel and endogenous (9). Unlike the chain structure of linear RNAs, circRNA has a circular structure such that the 3'- and 5'- ends are covalently linked based on the “back-splicing” reaction (10,11). Recent studies report that circRNA is a kind of closed-loop singled-stranded structural RNA with neither 5'-3' polarities nor polyadenylated tails. Due to this special structure, circRNA is regarded as a promising biomarker. Indeed, since the rapid expansion of RNA sequencing technology, circRNA has garnered considerable research intensity both in China and the international sphere.
History of circular RNA
In 1976, a single-chain covalent closed-loop molecule in plant-infected viroids was identified by electron microscopy; this was the first circRNA found in the world (12). With the discovery of pre-mRNA splicing in 1977, the presence of exon and introns was also soon realized (13,14). In 1987, an RNA loop was observed which was thought to be the splicing of the 5' splice site downstream of the 3' splice site in the splicing substrate of group I (15). The expression of this kind of RNA loop is expressed in E. coli and yeast (16). In addition, circRNAs have been reported to be more stable in vivo than linear RNAs because of the resistance to end-dependent degradation (17).
Despite these discoveries, circRNAs were misunderstood as an “unexpected product” in the splicing of pre-mRNA in the nucleus for a long time—so-called “transcriptional noise” or “transcriptional trash”. Thus, circRNAs did not receive much attention at that time (18,19). In recent years, with the technological surge in RNA sequencing, a large amount of RNA sequence data have been generated. Based on these “unexpected products”, a large number of circRNAs were discovered in various organisms, such as humans, mice, nematodes, zebrafish, and yeast (20-22).
Sources and characteristics of circular RNA
CircRNAs are derived from protein-coding genes, and the pre-mRNA is linked in a “head-to-tail” manner by linear RNA, which is generated by non-classical selective cleavage. It is commonly understood that the splicing of pre-mRNA includes three of the following ligation forms (23): (I) the 5'- splice site being ligated to the downstream 3'- splice site; (II) the 5'- splice site being ligated to the upstream 3'- splicing site; (III) the downstream 5'- splice site being ligated to the upstream 3'- splice site head to tail, i.e., RNA cyclization. Therefore, some believe that during the transcription of pre-mRNA, the RNA is partially folded, and thus the distance between non-adjacent exons is narrowed and exon skipping occurs. These two exons form a circular intermediate, which subsequently turns into circRNA (18,24-28).
Although most circRNAs are derived from exons, circRNAs are mainly classified into five classes according to the different sources of circRNA (29,30): (I) exon-derived circRNAs (ecircRNAs) which are the largest type of circRNAs, accounting for more than 80% of the discovered circRNA; (II) intron-derived circRNAs (EIciRNAs); (III) intergenomic circRNA which includes viroid and hepatitis D virus; (IV) circRNA intermediates during RNA processing which includes circRNA intermediates in tRNA or human RNA processing; (V) circRNA with housekeeping gene function (ciRNAs) which includes RnaseP or some snoRNAs.
CircRNAs have the following characteristics: (I) high stability; since circRNA is a covalently closed-loop singled-stranded structural RNA without 3'-end cap and 5'-end polyadenylated tails, circRNAs cannot be degraded by debranched enzyme and endonuclease, and so circRNAs can avoid normal RNA conversion pathways. Thus, circRNA is more stable than the homologous linear RNA. It has been reported that the average half-life of circRNAs can exceed 48 h, while the average half-life of linear RNA is about 10 h in most species (23). (II) High abundance; due to the high stability of circRNA, circRNA is more abundant and widely distributed than linear RNA. (III) High conservation; among different species, the mutation rate of circRNA is relatively low (20). (IV) Prevalence in cytoplasm; most circRNAs are present in the cytoplasm and regulate the expression of the target genes (9,24,31,32).
Biological functions of circular RNA
Views concerning the function of circRNA have gradually changed from “unexpected product of the pro-mRNA splicing” to “important regulatory non-coding RNA”.
Circular RNA acts as a miRNA sponge
In 2013, circRNA was firstly reported to function as an miRNA sponge in mammals. The natural antisense transcript of cerebellar degeneration-associated protein 1 (CDR1as), also known as ciRS-7, was found to tightly bind to the effector complex of miR-7 and inhibit its function, similarly to miR-7 knockdown (9). Following this discovery, the testis-specific circRNA, sex determining region Y (Sry) was found to act as a miR-138 sponge (32). Interestingly, CDR1as was found to be able to be degraded by miR-671 in some special situations, indicating that miR-671 indirectly regulates miR-7 expression via CDR1as (34). Moreover, the itchy E3 ubiquitin ligand (ITCH) is the parental gene of circ-ITCH, and the 3'-end of ITCH contains a miRNA binding site. circ-ITCH can also act as a miRNA sponge through the interaction with miR-7, miR-17, and miR-124 and ultimately regulate the expression of ITCH (35).
Circular RNA is involved in regulation of alternative splicing and transcription
Several studies have shown that circRNA is involved in the regulation of alternative splicing and transcription. Mannose-binding lectin (MBL) was found to be an RNA splicing factor that bound to its parental gene exon 2 and promoted its cyclization to form circMBL (10). CircMBL and its intron sequences contain a conserved binding site for MBL, which promotes circMBL production when MBL is increased. At the same time, circMBL combines with excess MBL and clears it to ensure a relatively stable level of MBL. It was also reported that there were many single exon-derived circRNAs in human fibroblasts, and each contains translation initiation sites (36). This means that these circRNAs can regulate the transcription process of target genes by translational isolation.
Circular RNA regulates the expression of parental genes
In addition to the aforementioned circ-ITCH which can regulate the expression of the parental gene ITCH through the interaction with some miRNAs, there is also a part of circRNA which regulates the expression of its parental genes by other means. Intron-derived EIciRNAs are mainly found in the nucleus and interact with U1 small nuclear RNA protein particles (U1 snRNP) and RNA polymerase II (Pol II) to regulate the expression of parental genes (31,37,38).
Circular RNA participates in protein translation
Recently, circRNA was found to be capable of encoding proteins as mRNA. A translation initiation site was found in circRNA sequence, which means that circRNA is capable of translation (36). The circRNA in the hepatitis D virus (HDV) is the first naturally occurring circRNA that can encode protein found in eukaryotic cells (39). The initiation process of circRNA encoding protein was also found to be enhanced by the basic modification of RNA by N6 methyladenosine (m6A) (16).
CircRNA and cancer
CircRNAs have a variety of biological functions, particularly in regulating gene expression. Through these biological functions, circRNAs are also involved in the occurrence and development of various diseases (40). The role of circRNA in the development of different cancers has also been investigated. Previous studies have shown that circRNA can widely regulate the function of cancer cells, and the expression of circRNAs changes in tumor tissues and/or circulating blood. Moreover, circRNA is closely related to the pathogenesis of neoplastic diseases. Most studies have reported that circRNAs acted as an miRNA sponge influencing cancer cell proliferation, epithelial-mesenchymal transition (EMT), and angiogenesis. circRNA may affect cancer cell apoptosis as well.
In Table 1, we listed the latest studies of some circRNAs in different cancers, including the circRNA function and mechanism of action during tumorigenesis and development.
Circulating circRNA and cancer
circRNAs have covalent circular structure in the absence of 3'-end and 5'-end. circRNAs exist stably and abundantly in circulating blood, especially in serum exosomes (67). As a result, circulating circRNAs are considered to be promising biomarkers in different cancers.
Studies based on a large number of serum samples from gastric cancer patients have shown that the serum level of circ-SFMBT2 (68) is up-regulated, while some circRNAs are down-regulated, including hsa_circ_0000745 (69), hsa_circ_0000181 (70), hsa_circ_0001649 (71), hsa_circ_0000190 (72), and hsa_circ_002059 (73). These circRNAs are expected to become the potential biomarkers of gastric cancer. Apart from gastric cancer, hsa_circ_0001649 was also negatively correlated with the degree of pathological differentiation of colorectal cancer patients (74). In the tumor tissues and serum samples of hepatocellular carcinoma patients, the level of circSMARCA5 (hsa_circ_0001445) is reduced; meanwhile, when combined with AFP, it can diagnose hepatocellular carcinoma more sensitively (75). Some circulating circRNAs were also changed in patients with pancreatic tumors. The elevation of serum circ-PDE8A suggests cancer progression and poor prognosis of PDAC patients (76). Serum circ-LDLRAD3 (77) is associated with venous invasion, lymphatic invasion, and metastasis of pancreatic cancer, while serum circ-IARS (78) is also closely related to liver metastasis, vascular invasion, and tumor-node-metastasis (TNM) stage. In addition to cancer progression, circulating circRNAs are associated with cancer phenotypes and can guide clinical treatment interventions. F-circEA has been reported to elevate in EML4-ALK fusion gene positive NSCLC patients’ serum (79). Overwhelming evidence has indicated that increasing serum circBA9.3 in chronic myeloid leukemia patients leads to tyrosine kinase inhibitor resistance (80). Furthermore, nasopharyngeal carcinoma patients with increased serum hsa_circ_0000285 showed lower sensitivity to radiotherapy and five-year survival rate (81).
FECR is an exon circRNA of Friend leukemia virus integration 1 (FLI1), which inactivates the tumor suppressor miR-584-3p, subsequently resulting in the activation of Rho-associated coiled-coil containing protein kinase 1 gene (ROCK1) (82). Clinically, tracking serum FECR level can monitor small cell lung cancer (SCLC) progression (82). Hsa_circ_0109046 and hsa_circ_0002577 were found to be differentially expressed in endometrial cancer patient serum, indicating that these two circRNAs may be potential biomarkers for predicting the progression and prognosis of endometrial cancer (83). The serum circPTK2 (84) (hsa_circ_0003221) increased in bladder cancer patients and the postoperative serum hsa_circ_0001785 (85) decreased in breast cancer patients, which confirmed the diagnostic value of serum circRNA in neoplastic diseases. The circulating circRNAs in cancers are summarized in Table 2.
This review summarized the characteristics and biological functions of circRNAs, and the relevant studies concerning circulating circRNAs acting as cancer biomarkers. The high stability and conservation of circRNAs make them promising biomarkers. However, standard protocol should be fixed so that studies from different groups can be compared. In addition, the source and function of circulating circRNAs should be investigated. Moreover, studies based on multiple centers should also be conducted.
Funding: This work is supported by grants from the National Natural Science Foundation of China (81873578 and 81400635 to F Wang), the Shanghai Medical Guide Project from Shanghai Science and Technology Committee (14411971500 to F Wang), and grants from the Chinese Foundation for Hepatitis Prevention and Control (TQGB20140141 to F Wang).
Conflicts of Interest: The authors have no conflicts of interest to declare.
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Cite this article as: Lu X, Song M, Wang F. Circulating circular RNAs as biomarkers of cancer. Non-coding RNA Investig 2019;3:8.