Circulating circular RNAs as biomarkers of cancer
Review Article

Circulating circular RNAs as biomarkers of cancer

Xiya Lu, Meiyi Song, Fei Wang

Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China

Contributions: (I) Conception and design: F Wang; (II) Administrative support: F Wang; (III) Provision of study materials or patients: F Wang; (IV) Collection and assembly of data: XY Lu, MY Song; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Dr. Fei Wang. Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xin Cun Road, Shanghai 200065, China. Email: 1132469@tongji.edu.cn.

Abstract: Circular RNA (circRNA) is a kind of novel non-coding RNA, which is widely present in eukaryotes and has a special circular structure formed by 3'- and 5'-ends linking covalently. CircRNA has many features, including high stability, conservation, etc. Since the discovery of circRNA, it has been considered a “by-product” of gene expression. In recent years, many studies have confirmed that circRNAs play an essential role in the pathogenesis of many diseases. CircRNA is involved in various cancer processes including the regulation of cell growth, proliferation, invasion, metastasis, etc., and is differentially expressed in tumor tissues and even in the circulation of patients. Because of these characteristics, circRNA has become a competitive candidate in being a novel biomarker of cancer. This article reviews the role of circulating circRNA in cancer and its diagnostic significance.

Keywords: Circular RNA; circulation; biomarker; cancer

Received: 15 January 2019; Accepted: 15 February 2019; Published: 28 February 2019.

doi: 10.21037/ncri.2019.02.01

Introduction

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

CircRNAs with an miRNA binding site competitively bind to miRNAs and reduce the effect of the miRNA on target genes, thereby indirectly regulating the expression of target genes (32,33).

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.

Table 1

CircRNAs involved in the pathogenesis of different cancers

Change in cancer Cancer Name of circRNAs Function Related molecules, signaling pathways and mechanism Ref.
Up-regulated Breast cancer FECR1 Promotes metastasis TET1, DNMT1, FLI1 (41)
CircANKS1B/hsa_circ_0007294 Promotes EMT, invasion and metastasis miR-148a-3p, miR-152-3p, USF1, TGF-β1/Smad pathway (42)
Circ-DNMT1 Promotes cell growth and proliferation; inhibits cell senescence p53, AUF1, autophagy (43)
CircAGFG1,hsa_circ_0058514 Promotes cell proliferation, migration and invasion; promotes tumorigenesis, angiogenesis and metastasis; inhibits cell apoptosis miR-195-5p, CCNE1 (triple-negative breast cancer) (44)
CircEPSTI1,hsa_circ_000479 Promotes cell proliferation; inhibits cell apoptosis miR-4753, miR-6809, BCL11A (triple-negative breast cancer) (45)
Hepatocellular carcinoma CircHIPK3 Promotes cell growth and proliferation miR-124, IL6R, DLX2 (46)
Cul2 circular RNA, circ-10720 Promotes EMT and metastasis; positively correlates with tumor malignancy Twist1, vimentin (EMT related protein) (47)
CircFBLIM1 Promotes cell proliferation and invasion; inhibits cell apoptosis miR-346, FBLIM1 (48)
Glioma Circ-DICER1 Promotes cell viability, migration and angiogenesis RNA-binding protein MOV10, miR-103a-3p, miR-382-5p, ZIC4, Hsp90β, PI3K/Akt pathway (49)
Bladder epithelial carcinoma CircPRMT5 Promotes EMT and invasion miR-30c, SNAIL1 (50)
Glioblastoma CircNT5E, hsa_circ_0077232 Promotes cell proliferation, migration and invasion; inhibits cell apoptosis RNA editing enzyme ADAR2, miR-422a (51)
Glioblastoma multiforme CircMMP9 Promotes cell proliferation, migration and invasion miR-124, cyclin-dependent kinase 4 (CDK4), aurora kinase A (AURKA), eukaryotic initiation factor 4A3 (eIF4A3) (52)
Non-small cell lung cancer (NSCLC) CircPTK2, hsa_circ_0008305 Promotes EMT and invasion miR-429, miR-200b-3p, TIF1γ, TGF-β (53)
Osteosarcoma CircFAT1 Promotes cell growth, migration, invasion and tumorigenesis miR-375, Yes-associated protein 1 (YAP1) (54)
Pancreatic ductal adenocarcinoma (PDAC) hsa_circ_0000977 Promotes PDAC progression miR-874-3P, PLK1 (55)
Multiple cancer cell lines Circ-CTNNB1 Promotes cell migration, invasion and tumor growth DEAD-box polypeptide 3 (DDX3), Yin Yang 1 (YY1), β-catenin (56)
Down-regulated Glioma CircPINTexon2 Inhibits cell proliferation PINT87aa, PAF1 complex, Pol II (57)
Hepatocellular Carcinoma cSMARCA5 Inhibits cell growth and migration miR-17-3p, miR-181b-5p, TIMP3 (58)
CircMTO1, hsa_circ_0007874, hsa_circ_104135 Inhibits cell proliferation and invasion miR-9, cyclin-dependent kinase inhibitor 1 (p21) (59)
Gastric carcinoma CircYAP1 Inhibits cell growth and invasion miR-367-5p, p27 Kip1 (60)
CircFAT1 (e2),hsa_circ_0001461 Inhibits cell proliferation, migration and invasion miR-548g, RUNX1, Y-box binding protein-1 (YBX1) (61)
Bladder cancer BCRC-3 Inhibits cell proliferation miR-182-5p, p27 (62)
CircFNDC3B Inhibits cell proliferation, migration and invasion miR-1178-3p, G3BP2, RC/FAK pathway (63)
Circ-ITCH Inhibits cell proliferation, migration, invasion and metastasis miR-17, miR-224, p21, PTEN (64)
Renal clear cell carcinoma CircATP2B1,hsa_circ_000826 Inhibits invasion and metastasis ERβ, miR-204-3p, FN1 (65)
Multiple cancer cell lines CircFoxo3 Inhibits cell cycle progression cyclin-dependent kinase 2/cell division protein kinase 2 (CDK2), p21 (66)

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.

Table 2

Circulating circRNAs change in cancers

Cancer type Name of circRNAs Change in cancer Diagnostic significance ROC curve Ref.
Gastric cancer Circ-SFMBT2 Up Associated with TNM stage – (68)
hsa_circ_0000745 Down Associated with pathological differentiation not tumor size, lymphatic metastasis, and TNM stage (I) Serum circRNA; AUC value: 0.683; Sensitivity: 0.855; Specificity: 0.45 (69)
(II) Combined with CEA; AUC value: 0.775; Sensitivity: 0.800; Specificity: 0.633
hsa_circ_0000181 Down Associated with tumor size, distal metastasis and lymphatic metastasis AUC value: 0.582; Specificity: 0.206; Sensitivity: 0.990 (70)
hsa_circ_0001649 Down Associated with pathological differentiation AUC value: 0.834; Sensitivity: 0.711; Specificity: 0.816 (71)
hsa_circ_0000190 Down Associated with distant metastasis and advanced cancer (I) Serum circRNA; AUC value: 0.60; Sensitivity: 0.414; Specificity: 0.875 (72)
(II) Combined with tissue circRNA; AUC value: 0.78; Sensitivity: 0.712; Specificity: 0.750
hsa_circ_002059 Down Associated with TNM stage and distant metastasis AUC value: 0.73; Sensitivity: 0.81; Specificity: 0.62 (73)
Colorectal cancer hsa_circ_0001649 Down Associated with colorectal cancer pathological differentiation AUC value: 0.857; Sensitivity: 0.828; Specificity: 0.781 (74)
Hepatocellular carcinoma CircSMARCA5, hsa_circ_0001445 Down Associated with intrahepatic metastasis; differential diagnosis of hepatocellular carcinoma, cirrhosis, and hepatitis B (I) Serum circRNA; A. with health control, AUC value: 0.862, Sensitivity 0.942, Specificity 0.712B. with liver cirrhosis,AUC value: 0.672; C. with hepatitis B, AUC value: 0.764 (75)
(II) Combined with AFP; A. with health control, AUC value: 0.970; B. with liver cirrhosis, AUC value: 0.743; C. with hepatitis B, AUC value: 0.877
Pancreatic tumor Circ-PDE8A Up Associated with tumor progression and prognosis of PDAC – (76)
Circ-LDLRAD3 Up Associated with venous invasion, lymphatic invasion, and metastasis of pancreatic cancer (I) Serum circRNA; AUC value: 0.67; Sensitivity: 0.5738; Specificity: 0.7049 (77)
(II) Combined with CA199; AUC value: 0.87; Sensitivity 0.8033; Specificity 0.9355
Circ-IARS Up Associated with liver metastasis, vascular invasion, TNM stage, and postoperative survival time of pancreatic cancer – (78)
Lung cancer F-circEA Up (EML4-ALK (+) NSCLC) Detection of EML4-ALK fusion gene in EML4-ALK positive NSCLC – (79)
FECR Up Associated with disease progression and lymphatic metastasis in SCLC – (82)
Leukemia CircBA9.3 Up Associated with prognosis and tyrosine kinase inhibitor (TKI) resistance in patients with chronic myeloid leukemia – (80)
Endometrial cancer hsa_circ_0109046 Up Associated with the occurrence, metastasis, and prognosis of endometrial cancer – (83)
hsa_circ_0002577 Up Associated with the occurrence, metastasis, and prognosis of endometrial cancer – (83)
Bladder cancer CircPTK2,hsa_circ_0003221 Up Associated with pathological differentiation, lymphatic metastasis, and TNM stage – (84)
Breast cancer hsa_circ_0001785 Down(Postoperative) Associated with pathological differentiation, TNM stage, and distant metastasis (I) Serum circRNA; AUC value: 0.784; Sensitivity: 0.764; Specificity: 0.699 (85)
(II) Combined with CEA and CA153; AUC value: 0.839; Sensitivity: 0.758; Specificity: 0.904
Nasopharyngeal carcinoma hsa_circ_0000285 Up Associated with radiosensitivity and five-year survival rate of patients – (81)

Conclusions

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.

Acknowledgments

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).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/ncri.2019.02.01). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Ponting CP, Belgard TG. Transcribed dark matter: meaning or myth? Hum Mol Genet 2010;19:R162-8. [Crossref] [PubMed]
  2. Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature 2012;489:57-74. [Crossref] [PubMed]
  3. International Human Genome Sequencing C. Finishing the euchromatic sequence of the human genome. Nature 2004;431:931-45. [Crossref]
  4. Wagner LA, Christensen CJ, Dunn DM, et al. EGO, a novel, noncoding RNA gene, regulates eosinophil granule protein transcript expression. Blood 2007;109:5191-8. [Crossref] [PubMed]
  5. Klattenhoff CA, Scheuermann JC, Surface LE, et al. Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell 2013;152:570-83. [Crossref] [PubMed]
  6. Yildirim E, Kirby JE, Brown DE, et al. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 2013;152:727-42. [Crossref] [PubMed]
  7. Quagliata L, Matter MS, Piscuoglio S, et al. Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. Hepatology 2014;59:911-23. [Crossref] [PubMed]
  8. Sana J, Faltejskova P, Svoboda M, et al. Novel classes of non-coding RNAs and cancer. J Transl Med 2012;10:103. [Crossref] [PubMed]
  9. Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 2013;495:333-8. [Crossref] [PubMed]
  10. Ashwal-Fluss R, Meyer M, Pamudurti NR, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell 2014;56:55-66. [Crossref] [PubMed]
  11. Barrett SP, Wang PL, Salzman J. Circular RNA biogenesis can proceed through an exon-containing lariat precursor. Elife 2015;4:e07540 [Crossref] [PubMed]
  12. Sanger HL, Klotz G, Riesner D, et al. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci U S A 1976;73:3852-6. [Crossref] [PubMed]
  13. Berget SM, Moore C, Sharp PA. Spliced segments at the 5' terminus of adenovirus 2 late mRNA. Proc Natl Acad Sci U S A 1977;74:3171-5. [Crossref] [PubMed]
  14. Chow LT, Gelinas RE, Broker TR, et al. An amazing sequence arrangement at the 5' ends of adenovirus 2 messenger RNA. Cell 1977;12:1-8. [Crossref] [PubMed]
  15. Price JV, Engberg J, Cech TR. 5' exon requirement for self-splicing of the Tetrahymena thermophila pre-ribosomal RNA and identification of a cryptic 5' splice site in the 3' exon. J Mol Biol 1987;196:49-60. [Crossref] [PubMed]
  16. Yang Y, Fan X, Mao M, et al. Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Res 2017;27:626-41. [Crossref] [PubMed]
  17. Puttaraju M, Perrotta AT, Been MD. A circular trans-acting hepatitis delta virus ribozyme. Nucleic Acids Res 1993;21:4253-8. [Crossref] [PubMed]
  18. Cocquerelle C, Mascrez B, Hetuin D, et al. Mis-splicing yields circular RNA molecules. FASEB J 1993;7:155-60. [Crossref] [PubMed]
  19. Wilusz JE A. 360 degrees view of circular RNAs: From biogenesis to functions. Wiley Interdiscip Rev RNA 2018;9:e1478 [Crossref] [PubMed]
  20. Jeck WR, Sorrentino JA, Wang K, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 2013;19:141-57. [Crossref] [PubMed]
  21. Danan M, Schwartz S, Edelheit S, et al. Transcriptome-wide discovery of circular RNAs in Archaea. Nucleic Acids Res 2012;40:3131-42. [Crossref] [PubMed]
  22. Singh SK, Gurha P, Tran EJ, et al. Sequential 2'-O-methylation of archaeal pre-tRNATrp nucleotides is guided by the intron-encoded but trans-acting box C/D ribonucleoprotein of pre-tRNA. J Biol Chem 2004;279:47661-71. [Crossref] [PubMed]
  23. Pasman Z, Garcia-Blanco MA. Early history of circular RNAs, children of splicing. RNA Biol 2017;14:975-7. [Crossref] [PubMed]
  24. Zaphiropoulos PG. Circular RNAs from transcripts of the rat cytochrome P450 2C24 gene: correlation with exon skipping. Proc Natl Acad Sci U S A 1996;93:6536-41. [Crossref] [PubMed]
  25. Caldas C, So CW, MacGregor A, et al. Exon scrambling of MLL transcripts occur commonly and mimic partial genomic duplication of the gene. Gene 1998;208:167-76. [Crossref] [PubMed]
  26. Surono A, Takeshima Y, Wibawa T, et al. Circular dystrophin RNAs consisting of exons that were skipped by alternative splicing. Hum Mol Genet 1999;8:493-500. [Crossref] [PubMed]
  27. Chao CW, Chan DC, Kuo A, et al. The mouse formin (Fmn) gene: abundant circular RNA transcripts and gene-targeted deletion analysis. Mol Med 1998;4:614-28. [Crossref] [PubMed]
  28. Burd CE, Jeck WR, Liu Y, et al. Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS Genet 2010;6:e1001233 [Crossref] [PubMed]
  29. Wang F, Nazarali AJ, Ji S. Circular RNAs as potential biomarkers for cancer diagnosis and therapy. Am J Cancer Res 2016;6:1167-76. [PubMed]
  30. Lyu D, Huang S. The emerging role and clinical implication of human exonic circular RNA. RNA Biol 2017;14:1000-6. [Crossref] [PubMed]
  31. Qu S, Yang X, Li X, et al. Circular RNA: A new star of noncoding RNAs. Cancer Lett 2015;365:141-8. [Crossref] [PubMed]
  32. Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges. Nature 2013;495:384-8. [Crossref] [PubMed]
  33. Shi X, Sun M, Liu H, et al. Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett 2013;339:159-66. [Crossref] [PubMed]
  34. Hansen TB, Kjems J, Damgaard CK. Circular RNA and miR-7 in cancer. Cancer Res 2013;73:5609-12. [Crossref] [PubMed]
  35. Li F, Zhang L, Li W, et al. Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/beta-catenin pathway. Oncotarget 2015;6:6001-13. [PubMed]
  36. Jeck WR, Sharpless NE. Detecting and characterizing circular RNAs. Nat Biotechnol 2014;32:453-61. [Crossref] [PubMed]
  37. Conn SJ, Pillman KA, Toubia J, et al. The RNA binding protein quaking regulates formation of circRNAs. Cell 2015;160:1125-34. [Crossref] [PubMed]
  38. Li Z, Huang C, Bao C, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol 2015;22:256-64. [Crossref] [PubMed]
  39. Alves C, Branco C, Cunha C. Hepatitis delta virus: a peculiar virus. Adv Virol 2013;2013:560105 [Crossref] [PubMed]
  40. Li J, Yang J, Zhou P, et al. Circular RNAs in cancer: novel insights into origins, properties, functions and implications. Am J Cancer Res 2015;5:472-80. [PubMed]
  41. Chen N, Zhao G, Yan X, et al. A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1. Genome Biol 2018;19:218. [Crossref] [PubMed]
  42. Zeng K, He B, Yang BB, et al. The pro-metastasis effect of circANKS1B in breast cancer. Mol Cancer 2018;17:160. [Crossref] [PubMed]
  43. Du WW, Yang W, Li X, et al. A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy. Oncogene 2018;37:5829-42. [Crossref] [PubMed]
  44. Yang R, Xing L, Zheng X, et al. The circRNA circAGFG1 acts as a sponge of miR-195-5p to promote triple-negative breast cancer progression through regulating CCNE1 expression. Mol Cancer 2019;18:4. [Crossref] [PubMed]
  45. Chen B, Wei W, Huang X, et al. circEPSTI1 as a Prognostic Marker and Mediator of Triple-Negative Breast Cancer Progression. Theranostics 2018;8:4003-15. [Crossref] [PubMed]
  46. Zheng Q, Bao C, Guo W, et al. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun 2016;7:11215. [Crossref] [PubMed]
  47. Meng J, Chen S, Han JX, et al. Twist1 Regulates Vimentin through Cul2 Circular RNA to Promote EMT in Hepatocellular Carcinoma. Cancer Res 2018;78:4150-62. [Crossref] [PubMed]
  48. Bai N, Peng E, Qiu X, et al. circFBLIM1 act as a ceRNA to promote hepatocellular cancer progression by sponging miR-346. J Exp Clin Cancer Res 2018;37:172. [Crossref] [PubMed]
  49. He Q, Zhao L, Liu X, et al. MOV10 binding circ-DICER1 regulates the angiogenesis of glioma via miR-103a-3p/miR-382-5p mediated ZIC4 expression change. J Exp Clin Cancer Res 2019;38:9. [Crossref] [PubMed]
  50. Chen X, Chen RX, Wei WS, et al. PRMT5 Circular RNA Promotes Metastasis of Urothelial Carcinoma of the Bladder through Sponging miR-30c to Induce Epithelial-Mesenchymal Transition. Clin Cancer Res 2018;24:6319-30. [Crossref] [PubMed]
  51. Wang R, Zhang S, Chen X, et al. CircNT5E Acts as a Sponge of miR-422a to Promote Glioblastoma Tumorigenesis. Cancer Res 2018;78:4812-25. [Crossref] [PubMed]
  52. Wang R, Zhang S, Chen X, et al. EIF4A3-induced circular RNA MMP9 (circMMP9) acts as a sponge of miR-124 and promotes glioblastoma multiforme cell tumorigenesis. Mol Cancer 2018;17:166. [Crossref] [PubMed]
  53. Wang L, Tong X, Zhou Z, et al. Circular RNA hsa_circ_0008305 (circPTK2) inhibits TGF-beta-induced epithelial-mesenchymal transition and metastasis by controlling TIF1gamma in non-small cell lung cancer. Mol Cancer 2018;17:140. [Crossref] [PubMed]
  54. Liu G, Huang K, Jie Z, et al. CircFAT1 sponges miR-375 to promote the expression of Yes-associated protein 1 in osteosarcoma cells. Mol Cancer 2018;17:170. [Crossref] [PubMed]
  55. Huang WJ, Wang Y, Liu S, et al. Silencing circular RNA hsa_circ_0000977 suppresses pancreatic ductal adenocarcinoma progression by stimulating miR-874-3p and inhibiting PLK1 expression. Cancer Lett 2018;422:70-80. [Crossref] [PubMed]
  56. Yang F, Fang E, Mei H, et al. Cis-Acting circ-CTNNB1 Promotes beta-Catenin Signaling and Cancer Progression via DDX3-Mediated Transactivation of YY1. Cancer Res 2019;79:557-71. [Crossref] [PubMed]
  57. Zhang M, Zhao K, Xu X, et al. A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun 2018;9:4475. [Crossref] [PubMed]
  58. Yu J, Xu QG, Wang ZG, et al. Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma. J Hepatol 2018;68:1214-27. [Crossref] [PubMed]
  59. Han D, Li J, Wang H, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology 2017;66:1151-64. [Crossref] [PubMed]
  60. Liu H, Liu Y, Bian Z, et al. Circular RNA YAP1 inhibits the proliferation and invasion of gastric cancer cells by regulating the miR-367-5p/p27 (Kip1) axis. Mol Cancer 2018;17:151. [Crossref] [PubMed]
  61. Fang J, Hong H, Xue X, et al. A novel circular RNA, circFAT1(e2), inhibits gastric cancer progression by targeting miR-548g in the cytoplasm and interacting with YBX1 in the nucleus. Cancer Lett 2019;442:222-32. [Crossref] [PubMed]
  62. Xie F, Li Y, Wang M, et al. Circular RNA BCRC-3 suppresses bladder cancer proliferation through miR-182-5p/p27 axis. Mol Cancer 2018;17:144. [Crossref] [PubMed]
  63. Liu H, Bi J, Dong W, et al. Invasion-related circular RNA circFNDC3B inhibits bladder cancer progression through the miR-1178-3p/G3BP2/SRC/FAK axis. Mol Cancer 2018;17:161. [Crossref] [PubMed]
  64. Yang C, Yuan W, Yang X, et al. Circular RNA circ-ITCH inhibits bladder cancer progression by sponging miR-17/miR-224 and regulating p21, PTEN expression. Mol Cancer 2018;17:19. [Crossref] [PubMed]
  65. Han Z, Zhang Y, Sun Y, et al. ERbeta-Mediated Alteration of circATP2B1 and miR-204-3p Signaling Promotes Invasion of Clear Cell Renal Cell Carcinoma. Cancer Res 2018;78:2550-63. [Crossref] [PubMed]
  66. Du WW, Yang W, Liu E, et al. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res 2016;44:2846-58. [Crossref] [PubMed]
  67. Li Y, Zheng Q, Bao C, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res 2015;25:981-4. [Crossref] [PubMed]
  68. Sun H, Xi P, Sun Z, et al. Circ-SFMBT2 promotes the proliferation of gastric cancer cells through sponging miR-182-5p to enhance CREB1 expression. Cancer Manag Res 2018;10:5725-34. [Crossref] [PubMed]
  69. Huang M, He YR, Liang LC, et al. Circular RNA hsa_circ_0000745 may serve as a diagnostic marker for gastric cancer. World J Gastroenterol 2017;23:6330-8. [Crossref] [PubMed]
  70. Zhao Q, Chen S, Li T, et al. Clinical values of circular RNA 0000181 in the screening of gastric cancer. J Clin Lab Anal 2018;32:e22333 [Crossref] [PubMed]
  71. Li WH, Song YC, Zhang H, et al. Decreased Expression of Hsa_circ_00001649 in Gastric Cancer and Its Clinical Significance. Dis Markers 2017;2017:4587698 [Crossref] [PubMed]
  72. Chen S, Li T, Zhao Q, et al. Using circular RNA hsa_circ_0000190 as a new biomarker in the diagnosis of gastric cancer. Clin Chim Acta 2017;466:167-71. [Crossref] [PubMed]
  73. Li P, Chen S, Chen H, et al. Using circular RNA as a novel type of biomarker in the screening of gastric cancer. Clin Chim Acta 2015;444:132-6. [Crossref] [PubMed]
  74. Ji W, Qiu C, Wang M, et al. Hsa_circ_0001649: A circular RNA and potential novel biomarker for colorectal cancer. Biochem Biophys Res Commun 2018;497:122-6. [Crossref] [PubMed]
  75. Zhang X, Zhou H, Jing W, et al. The Circular RNA hsa_circ_0001445 Regulates the Proliferation and Migration of Hepatocellular Carcinoma and May Serve as a Diagnostic Biomarker. Dis Markers 2018;2018:3073467 [Crossref] [PubMed]
  76. Li Z, Yanfang W, Li J, et al. Tumor-released exosomal circular RNA PDE8A promotes invasive growth via the miR-338/MACC1/MET pathway in pancreatic cancer. Cancer Lett 2018;432:237-50. [Crossref] [PubMed]
  77. Yang F, Liu DY, Guo JT, et al. Circular RNA circ-LDLRAD3 as a biomarker in diagnosis of pancreatic cancer. World J Gastroenterol 2017;23:8345-54. [Crossref] [PubMed]
  78. Li J, Li Z, Jiang P, et al. Circular RNA IARS (circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis. J Exp Clin Cancer Res 2018;37:177. [Crossref] [PubMed]
  79. Tan S, Gou Q, Pu W, et al. Circular RNA F-circEA produced from EML4-ALK fusion gene as a novel liquid biopsy biomarker for non-small cell lung cancer. Cell Res 2018;28:693-5. [Crossref] [PubMed]
  80. Pan Y, Lou J, Wang H, et al. CircBA9.3 supports the survival of leukaemic cells by up-regulating c-ABL1 or BCR-ABL1 protein levels. Blood Cells Mol Dis 2018;73:38-44. [Crossref] [PubMed]
  81. Shuai M, Hong J, Huang D, et al. Upregulation of circRNA_0000285 serves as a prognostic biomarker for nasopharyngeal carcinoma and is involved in radiosensitivity. Oncol Lett 2018;16:6495-501. [PubMed]
  82. Li L, Li W, Chen N, et al. FLI1 Exonic Circular RNAs as a Novel Oncogenic Driver to Promote Tumor Metastasis in Small Cell Lung Cancer. Clin Cancer Res 2019;25:1302-17. [Crossref] [PubMed]
  83. Xu H, Gong Z, Shen Y, et al. Circular RNA expression in extracellular vesicles isolated from serum of patients with endometrial cancer. Epigenomics 2018;10:187-97. [Crossref] [PubMed]
  84. Xu ZQ, Yang MG, Liu HJ, et al. Circular RNA hsa_circ_0003221 (circPTK2) promotes the proliferation and migration of bladder cancer cells. J Cell Biochem 2018;119:3317-25. [Crossref] [PubMed]
  85. Yin WB, Yan MG, Fang X, et al. Circulating circular RNA hsa_circ_0001785 acts as a diagnostic biomarker for breast cancer detection. Clin Chim Acta 2018;487:363-8. [Crossref] [PubMed]

(English Language Editor: John Ayric Gray, AME Publishing Company)

doi: 10.21037/ncri.2019.02.01
Cite this article as: Lu X, Song M, Wang F. Circulating circular RNAs as biomarkers of cancer. Non-coding RNA Investig 2019;3:8.

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