circRNAs may be found in serum, saliva and the exosomes of mammalian cells. Using a genome-wide approach, circRNAs were first detected in excised exons or introns (28) and were generally classified into three subtypes: Exonic circRNAs (ecircRNAs) (29), circular intronic RNAs (ciRNAs) (30), and exon-intron circRNAs (EIciRNAs) (31). Cytoplasmic ecircRNAs account for >90% of total circRNAs (11,13,21), whereas nuclear circRNAs are mainly ciRNAs and EIciRNAs (30,31), and exosomal circRNAs (exo-circRNAs), another type of circRNA, are distributed in the exosomes of human serum and in multiple human cancer cell lines (32).

To date, circRNAs have mainly been reported to form via back-splicing (22), which is characterized by the covalent binding of a 5′ splicing acceptor to a 3′ splicing donor (15). Jeck et al (13) proposed two models to assess the production of circRNAs; model one is referred to as ‘direct back-splicing’, while model two is termed ‘exon skipping’ or ‘lariat intermediate’. Generally, alternative circularization is generated from different numbers of exons (13,22,25,33), with or without an internal intron (14,22,31). Nevertheless, it remains unclear whether alternative circularization occurs co-transcriptionally or post-transcriptionally, and what factors affect circularization.

circRNAs exhibit specific characteristics distinct from linear RNAs. Firstly, circRNAs have particular covalently closed loop structures, rather than the typical 5′ caps and 3′ tails at the termini of linear RNAs (21,22), which render circRNAs more stable compared with their linear counterparts and more resistant to degradation by various endogenous RNA exonucleases (34,35). Additionally, certain circRNAs are widespread and more abundant compared with their linear counterparts (13,36). A previous study revealed that certain circRNAs were expressed in a cell type-specific manner; for example, hsa_circRNA_21 was only detected in cluster of differentiation (CD)19⁺ leukocytes and not in CD34⁺ leukocytes or neutrophils (11). The majority of circRNAs are evolutionarily conserved among different species (13,14,37), with the exception of intergenic or intronic circRNAs (30).

In a previous study on CRC, 39 differentially expressed circRNAs were identified between CRC and matched normal colonic mucosa tissues (43). In addition, the ratio of circRNAs to linear RNA counterparts was decreased in CRC tissues compared with that in normal colon tissues, and even further decreased in CRC cell lines compared with that in normal colon tissues. Furthermore, there was a negative correlation between this ratio and the proliferation index, which provided the basis to explore their functions and mechanisms in CRC. In addition, the authors hypothesized that their findings were due to the dysfunction of back-splicing or dysregulation of oncogenic miRNAs, resulting in the degradation and downregulation of circRNAs in CRC (43).

Similarly, itchy E3 ubiquitin protein ligase (ITCH) circRNA (circ-ITCH) expression was revealed to be significantly downregulated in CRC tissues compared with that in peritumoral tissues, and circ-ITCH could upregulate the expression of its linear counterpart, ITCH, and thereafter affect the Wnt/β-catenin signaling pathway in CRC (44). Additionally, decreased expression of hsa_circ_001988 was identified in CRC, and the expression of hsa_circ_001988 was significantly correlated with differentiation and perineural invasion of CRC cells (45). Dou et al (46) also revealed that numerous circRNAs are downregulated in KRAS proto-oncogene mutant colon cancer cells and may be transferred to exosomes, and that circRNAs were more abundant in exosomes compared with cells.

Qin et al (47) revealed that hsa_circ_0001649 expression was significantly decreased in HCC and may represent a novel biomarker for HCC. Xu et al (48) demonstrated that, although the expression of CDR1 antisense RNA (CDR1-AS; also known as ciRS-7) was comparable between HCC and matched non-tumor tissues, the increased ciRS-7 expression in HCC tissues was significantly correlated with hepatic microvascular invasion and therefore associated with the deterioration of HCC. Furthermore, circRNA profiling revealed that hsa_circ_0005075, a circRNA biomarker, exhibited a significant difference in expression between HCC and normal tissues, and a pathological correlation analysis indicated that hsa_circ_0005075 was associated with the development of HCC (49).

Li et al (50) demonstrated that the expression of circ-ITCH was downregulated in ESCC. Su et al (51) also performed expression profiling of circRNAs in radioresistant ESCC cells, and revealed that circRNA_001059 and circRNA_000167 were associated with the development of radiation resistance. In addition, Xia et al (52) demonstrated that, hsa_circ_0067934 expression was significantly upregulated in ESCC and could promote the proliferation of ESCC cells.

Expression patterns in CircNet revealed that expression of the circRNAs circ-zinc finger E-box binding homeobox (ZEB)1.5, circ-ZEB1.19, circ-ZEB1.17 and circ-ZEB1.33 were downregulated in lung cancer specimens compared with that in normal lung tissues (53). Another study demonstrated that the expression of circ-ITCH was significantly decreased in lung cancer tissue compared with normal lung tissue (54).

By microarray analysis, Qu et al (55) identified that numerous circRNAs were dysregulated in pancreatic ductal adenocarcinoma (PDAC), and these results implied their vital functions in the progression of PDAC.

Hsa_circ_002059, a representative circRNA, was downregulated in GC and its differential expression was significantly correlated with distal metastasis and tumor-node-metastasis stage (56), suggesting it could potentially serve as a diagnostic biomarker for GC.

Zhong et al (57) screened differential circRNA expression profiles in bladder carcinoma and revealed that the expression of family with sequence similarity 169 member A circRNA and tripartite motif-containing 24 circRNA were significantly downregulated in bladder carcinoma, while the expression levels of transcription factor (TCF)25 circRNA (circ-TCF25), zinc finger RNA-binding protein circRNA, protein tyrosine kinase 2 circRNA and BC048201 circRNA were significantly increased in carcinoma tissues. This suggested that circ-TCF25 could represent a novel biomarker for bladder cancer.

Ahmed et al (58) revealed that altered expression patterns of circRNAs were present in primary and metastatic sites of epithelial ovarian carcinoma. In addition, circRNA expression was inversely associated with linear RNA expression for numerous cancer-associated signaling pathways; the majority of these signaling pathways, such as the transforming growth factor β1 signaling pathway, were typically activated by linear RNA (mRNA) expression in metastases compared to primary site of origin, but repressed by circRNA expression (58).

Xuan et al (59) demonstrated that hsa_circ_100855 expression was significantly increased in laryngeal squamous cell cancer tissues compared with that in matched adjacent non-neoplastic tissues, and increased hsa_circ_100855 expression was revealed in patients with T3-4 stage disease, neck nodal metastasis, or advanced clinical stage. However, hsa_circ_104912 expression exhibited the reverse trend compared with hsa_circ_100855 (59).

In breast cancer, circRNA expression profiling results revealed that normal-adjacent tissues in patients with the estrogen receptor (ER)⁺ subtype were associated with an increased number of circRNAs compared with that in breast cancer tissues, and the number of circRNAs in normal-adjacent samples of ER⁺ subtype was inversely correlated with the risk-of-relapse proliferation score for proliferation-associated genes (60). Yang et al (61) revealed that zinc finger protein 292 circRNA could suppress human glioma tube formation via the Wnt/β-catenin signaling pathway and may potentially be applied as a therapeutic target and biomarker in glioma.

However, the association between certain circRNA and tumorigenesis is unclear and supported by sufficient evidence. Further studies will provide a more extensive awareness of circRNAs in different types of cancer, including their properties, functions and mechanisms.

miRNAs, a large class of sncRNAs, serve important functions in multiple types of cancer by repressing downstream cancer-associated mRNAs (63). Due to the complementarity between circRNAs and targeted genes, circRNAs may bind miRNAs and competitively suppress the function of targeted miRNAs, thereby permitting circRNAs to regulate the progression of cancer by sequestering specific miRNAs associated with proliferation, differentiation, metastasis and carcinogenesis.

Human ciRS-7/CDR1-AS is a typical example of a circRNA that functions as an miRNA sponge, and comprises as many as 74 miR-7-binding sites (11,19,62). miR-7 may serve as a tumor suppressor, and is downregulated in various types of cancer, including GC (64), HCC (65) and CRC (66). miR-7 is involved in numerous cancer-associated signaling pathways by downregulating the expression of crucial oncogenic factors, including Raf-1 proto-oncogene (67), mechanistic target of rapamycin (65) and signal transducer and activator of transcription 3 (68). Therefore, ciRS-7 could regulate cancer progression through miR-7-mediated downstream signaling pathways. However, other reports have revealed a tumor-promoting function of miR-7 in CRC (69), human papilloma virus-positive HeLa cells (70) and A549 cells (71). miR-7 is coupled to ciRS-7 through multiple miRNA response elements in ciRS-7, and ciRS-7 may either promote cancer progression or suppress carcinogenesis depending on the expression of miRNA targets (11,19,62).

Li et al (50) demonstrated that circ-ITCH may serve a tumor-suppressive function in ESCC and serve as a sponge for miR-7, miR-17 and miR-214, resulting in increased ITCH expression, thereby promoting ubiquitin-mediated degradation of disheveled segment polarity protein 2, and inhibiting the Wnt/β-catenin signaling pathway. This mechanism for circ-ITCH was also verified in lung cancer (54). Similarly, Yang et al (40) revealed that circ-FOXO3 may also function as a sponge of miRNAs to increase FOXO3 translation and thereby suppress tumor growth, cancer cell proliferation and survival. In addition, Zhong et al (57) demonstrated in bladder cancer that the overexpression of circ-TCF25 could decrease the expression of miR-103a-3p and miR-107, increase the expression of cyclin-dependent kinase (CDK)6 and promote the proliferation and migration of cancer cells in vitro and in vivo. Zheng et al (39) also revealed that circ-HIPK3 sponged 9 miRNAs and directly bound miR-124 and inhibited its activity.

Although multiple circRNAs have been demonstrated to regulate cancer progression in vitro or in vivo (53,17,72), certain predicted circRNAs remain to be validated. For example, Liu et al (53) proposed that circ-ZEB1.5, circ-ZEB1.19, circ-ZEB1.17 and circ-ZEB1.33 possess the potential to sponge miR-200. Zhang et al (17) revealed that circRNA_1093, with a short sequence of 108 bp, has 4 potential miR-342 binding sites, while miR-342 has been reported to regulate the expression of BRCA1 in breast cancer (72). These circRNAs require further study to confirm their function and molecular mechanisms. Certainly, the circRNAs that function as miRNA sponges provide a novel direction for diagnosing and treating multiple types of cancer and the circRNA-miRNA-gene regulatory networks in cancer require further study.

circRNAs have also been associated with another important function: Acting as RBP sponges to regulate downstream gene transcription (12). Multiple studies have indicated that certain circRNAs may be associated with RBPs, such as argonaute (AGO) proteins (11,19), Quaking (QKI) (73), RNA polymerase II (30), mannose-binding lectin 2 (74) and eukaryotic translation initiation factor 4A3 (75). These circRNAs can serve as carriers to store, sort or deliver RBPs to particular subcellular locations, or regulate the function of RBPs by functioning as ceRNAs (11,76). Certain RBPs serve key regulatory functions in cell proliferation, differentiation, apoptosis and migration (77,78). Their dysregulated expression may affect cancer development (79,80). For example, AGO proteins may regulate tumorigenesis via miRNA-dependent or independent signaling pathways and AGO2 was shown to be associated with cancer progression by interacting with RISC-loading complex subunit TARBP2 and endoribonuclease Dicer (81).

As an RBP, QKI-5 has been characterized as a novel tumor suppressor in multiple types of cancer. For example, QKI-5 has been demonstrated to inhibit the proliferation of lung cancer cells (82), and the proliferation, cell cycle progression and invasion of prostate cancer cells (83). Furthermore, QKI-5 was shown to regulate the formation of circRNAs, and the upregulation of the majority of circRNAs during the epithelial-mesenchymal transition (EMT) suggests they may serve a crucial function in EMT (73). Since EMT serves an important function in initiating metastasis (84,85), further study is required to elucidate the function of QKI-mediated circRNAs in cancer. In addition, Du et al (41) also revealed that circ-FOXO3 could decelerate cell cycle progression by forming ternary complexes with p21 and CDK2 proteins.

These studies suggest that RBPs and circRNAs could interact reciprocally to affect cancer progression.