Emerging Epigenetic Regulation of Circular RNAs in Human Cancer
2019; Cell Press; Volume: 16; Linguagem: Inglês
10.1016/j.omtn.2019.04.011
ISSN2162-2531
AutoresJie Wu, Xiaoqian Qi, Lina Liu, Xin Hu, Jingwen Liu, Jianming Yang, Jun Yang, Lu Lu, Zheng Zhang, Shiqing Ma, Hongfa Li, Xinyue Yun, Tong Sun, Yue Wang, Zuomin Wang, Zihao Liu, Wei Zhao,
Tópico(s)Cancer-related molecular mechanisms research
ResumoCircular RNAs (circRNAs) are novel members of the noncoding RNA family. Their characteristic covalent closed-loop structure endows circRNAs that are much more stable than the corresponding linear transcript. circRNAs are ubiquitous in eukaryotic cells, and their functions are diverse and include adsorbing microRNAs (miRNAs; acting as miRNA sponges), regulating transcription, interacting with RNA-binding proteins, and translating and deriving pseudogenes. Moreover, circRNAs are associated with the occurrence and progression of a variety of cancers, acting as new biomarkers for early diagnosis to evaluate curative effects and patient prognosis. Here, this paper briefly describes the characteristics and functions of circRNAs, and it further concludes the relationship between circRNAs and human cancer. Circular RNAs (circRNAs) are novel members of the noncoding RNA family. Their characteristic covalent closed-loop structure endows circRNAs that are much more stable than the corresponding linear transcript. circRNAs are ubiquitous in eukaryotic cells, and their functions are diverse and include adsorbing microRNAs (miRNAs; acting as miRNA sponges), regulating transcription, interacting with RNA-binding proteins, and translating and deriving pseudogenes. Moreover, circRNAs are associated with the occurrence and progression of a variety of cancers, acting as new biomarkers for early diagnosis to evaluate curative effects and patient prognosis. Here, this paper briefly describes the characteristics and functions of circRNAs, and it further concludes the relationship between circRNAs and human cancer. Based on the potential of encoded proteins, the RNA family can be divided into two categories, coding RNAs and noncoding RNAs; noncoding RNAs include long noncoding RNA, riRNA, tRNA, nsRNA, and microRNA (miRNA). In recent years, RNA research has made great progress in the identification of noncoding RNAs, which are involved in a variety of biological processes.1Wilusz J.E. Sharp P.A. Molecular biology. A circuitous route to noncoding RNA.Science. 2013; 340: 440-441Crossref PubMed Scopus (384) Google Scholar, 2Zhao W. Ma X. Liu L. Chen Q. Liu Z. Zhang Z. Ma S. Wang Z. Li H. Wang Z. Wu J. SNHG20: A vital lncRNA in multiple human cancers.J. Cell. Physiol. 2019; (Published online January 15, 2019)https://doi.org/10.1002/jcp.28143Crossref Scopus (47) Google Scholar Circular RNAs (circRNAs) have nearly 30 years of history. They are a special class of noncoding RNAs derived from the back-splicing or exon skipping of pre-mRNAs. Unlike linear RNAs, circRNAs do not have a 5-cap and 3-poly(A) tails, which are produced by back-splicing exons, and the downstream 3-splicing donor is connected in reverse bond to the upstream 5-split acceptor.3Pieler T. Theunissen O. TFIIIA: nine fingers--three hands?.Trends Biochem. Sci. 1993; 18: 226-230Abstract Full Text PDF PubMed Scopus (39) Google Scholar circRNAs are stable due to their special circular structure, and they are not easily degraded by exonucleases, thus having a longer half-life. circRNAs are considered inert by-products of abnormally spliced linear RNAs. With the emergence of high-throughput sequencing, an increasing number of circRNAs have been found in eukaryotic cells. Increasing evidence shows that the expression profiles of circRNAs in carcinoid tissues are different from those in normal tissues.4Shi P. Sun J. He B. Song H. Li Z. Kong W. Wang J. Wang J. Xue H. Profiles of differentially expressed circRNAs in esophageal and breast cancer.Cancer Manag. Res. 2018; 10: 2207-2221Crossref PubMed Scopus (35) Google Scholar, 5Cheng X.Y. Shen H. [Circular RNA in Lung Cancer Research: Biogenesis, Functions and Roles].Zhongguo Fei Ai Za Zhi. 2018; 21: 50-56PubMed Google Scholar In addition, circRNAs have been reported to participate in a variety of cellular cancer-related physiological processes, including cancer initiation, progression, and metastasis.6Qu S. Yang X. Li X. Wang J. Gao Y. Shang R. Sun W. Dou K. Li H. Circular RNA: A new star of noncoding RNAs.Cancer Lett. 2015; 365: 141-148Crossref PubMed Scopus (1222) Google Scholar Therefore, an in-depth analysis of circRNAs should help further clarify the epigenetic level of cancer-related mechanisms. According to their differences in the genome and constituent sequences, circRNAs can be divided into three categories: exon-derived circRNAs, intron-derived circRNAs, and circRNAs composed of exons and introns.7Ashwal-Fluss R. Meyer M. Pamudurti N.R. Ivanov A. Bartok O. Hanan M. Evantal N. Memczak S. Rajewsky N. Kadener S. circRNA biogenesis competes with pre-mRNA splicing.Mol. Cell. 2014; 56: 55-66Abstract Full Text Full Text PDF PubMed Scopus (1951) Google Scholar, 8Kelly S. Greenman C. Cook P.R. Papantonis A. Exon Skipping Is Correlated with Exon Circularization.J. Mol. Biol. 2015; 427: 2414-2417Crossref PubMed Scopus (245) Google Scholar, 9Chen I. Chen C.Y. Chuang T.J. Biogenesis, identification, and function of exonic circular RNAs.Wiley Interdiscip. Rev. RNA. 2015; 6: 563-579Crossref PubMed Scopus (281) Google Scholar Three models are used to illuminate the possible formation of circRNAs: lariat-driven circularization, intron pairing-driven circularization, and RNA-binding protein-driven circularization (Figure 1). During exon skipping (cassette-on), the spliced intron lariat still reserves the skipped exon(s). A stable RNA circle can be produced when further splicing occurs before the lariat is decomposed by debranching enzymes. Lariat-driven circularization is also known as the exon-skipping mechanism. The pre-mRNA partially folds during transcription, causing the 5′ splicing site (donor site) of the upstream intron to approach and attack the 3′ splicing site (receptor site) of the downstream intron, whereby the circRNA is formed by back-splicing of the folded region, while the remaining exons form a linear mRNA.10Jeck W.R. Sorrentino J.A. Wang K. Slevin M.K. Burd C.E. Liu J. Marzluff W.F. Sharpless N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA. 2013; 19: 141-157Crossref PubMed Scopus (2826) Google Scholar, 11Wilusz J.E. A 360° view of circular RNAs: From biogenesis to functions.Wiley Interdiscip. Rev. RNA. 2018; 9: e1478Crossref PubMed Scopus (300) Google Scholar This is the mechanism for the formation of most circRNAs. For example, Kelly et al.8Kelly S. Greenman C. Cook P.R. Papantonis A. Exon Skipping Is Correlated with Exon Circularization.J. Mol. Biol. 2015; 427: 2414-2417Crossref PubMed Scopus (245) Google Scholar found that human umbilical vein endothelial cells stimulated with tumor necrosis factor α or tumor growth factor β contained a large number of circRNAs formed by lariat-driven circularization. Intron pairing-driven circularization is also known as the direct back-splicing mechanism. Reverse complementary sequences on the flanks of introns mediate back-splicing to form circRNAs. Flanking complementary sequences (especially Alu sequences) play a crucial part in exon circularization, and perfectly matched complementary sequences can promote the expression of circRNAs.12Rybak-Wolf A. Stottmeister C. Glažar P. Jens M. Pino N. Giusti S. Hanan M. Behm M. Bartok O. Ashwal-Fluss R. et al.Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed.Mol. Cell. 2015; 58: 870-885Abstract Full Text Full Text PDF PubMed Scopus (1484) Google Scholar, 13Koh W. Pan W. Gawad C. Fan H.C. Kerchner G.A. Wyss-Coray T. Blumenfeld Y.J. El-Sayed Y.Y. Quake S.R. Noninvasive in vivo monitoring of tissue-specific global gene expression in humans.Proc. Natl. Acad. Sci. USA. 2014; 111: 7361-7366Crossref PubMed Scopus (200) Google Scholar In this procedure, circRNAs can be divided into two patterns according to whether partial intron sequences are retained, namely, exonic circRNAs (EcircRNAs) from exons and circRNAs that coexist between intron and exon sequences (EIciRNAs).14Bahn J.H. Zhang Q. Li F. Chan T.M. Lin X. Kim Y. Wong D.T. Xiao X. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva.Clin. Chem. 2015; 61: 221-230Crossref PubMed Scopus (489) Google Scholar Hsa-circ-POLR2A is a typical intron pairing-driven circRNA.13Koh W. Pan W. Gawad C. Fan H.C. Kerchner G.A. Wyss-Coray T. Blumenfeld Y.J. El-Sayed Y.Y. Quake S.R. Noninvasive in vivo monitoring of tissue-specific global gene expression in humans.Proc. Natl. Acad. Sci. USA. 2014; 111: 7361-7366Crossref PubMed Scopus (200) Google Scholar During RNA-binding protein-driven circularization, RNA-binding proteins (RBPs) can shorten the distance between the donor site and the receptor site by binding to the introns on the flanks, thus promoting the circularization of the exons. Muscleblind protein and quaking protein are two known RBPs that promote the formation of circMbl and circQKI, respectively.15Lasda E. Parker R. Circular RNAs: diversity of form and function.RNA. 2014; 20: 1829-1842Crossref PubMed Scopus (848) Google Scholar, 16Ivanov A. Memczak S. Wyler E. Torti F. Porath H.T. Orejuela M.R. Piechotta M. Levanon E.Y. Landthaler M. Dieterich C. Rajewsky N. Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals.Cell Rep. 2015; 10: 170-177Abstract Full Text Full Text PDF PubMed Scopus (673) Google Scholar Therefore, RBPs play a crucial role in the formation of some circRNAs. There are two hypotheses for the formation of exon-derived circRNAs. The first hypothesis is that the pre-mRNA crosses an exon during transcription, the splicing enzyme then cleaves at both ends of the crossed exon, and the two ends are connected to form a closed-loop structure (lariat);7Ashwal-Fluss R. Meyer M. Pamudurti N.R. Ivanov A. Bartok O. Hanan M. Evantal N. Memczak S. Rajewsky N. Kadener S. circRNA biogenesis competes with pre-mRNA splicing.Mol. Cell. 2014; 56: 55-66Abstract Full Text Full Text PDF PubMed Scopus (1951) Google Scholar therefore, multiple circRNAs are generated by splicing. circRNAs can be derived from a single exon by back-splicing and can also be formed by exon splicing. Another hypothesis is that, during RNA transcription, the introns at both ends of the exons are base-paired, the downstream exon's 3′ end tail is connected to the upstream exon's 5′ end head, the downstream 3′ spliceosome is bound to the upstream 5′ splicing receptor, resulting in the binding of the two introns, and the cyclized exons are released as a circRNA.8Kelly S. Greenman C. Cook P.R. Papantonis A. Exon Skipping Is Correlated with Exon Circularization.J. Mol. Biol. 2015; 427: 2414-2417Crossref PubMed Scopus (245) Google Scholar Many EcircRNAs contain exons that encode gene sequences and are normally spliced at standard splicing sites through the splicing copolymer mechanism. Genome-wide analysis of RNA sequencing (RNA-seq) data suggests that EcircRNAs are abundant in the mammalian transcriptome, and some EcircRNA sequences and their expression are conserved in evolutionary variation, revealing that they have cellular functions.10Jeck W.R. Sorrentino J.A. Wang K. Slevin M.K. Burd C.E. Liu J. Marzluff W.F. Sharpless N.E. Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA. 2013; 19: 141-157Crossref PubMed Scopus (2826) Google Scholar, 12Rybak-Wolf A. Stottmeister C. Glažar P. Jens M. Pino N. Giusti S. Hanan M. Behm M. Bartok O. Ashwal-Fluss R. et al.Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed.Mol. Cell. 2015; 58: 870-885Abstract Full Text Full Text PDF PubMed Scopus (1484) Google Scholar, 17Wilusz J.E. Circular RNAs: Unexpected outputs of many protein-coding genes.RNA Biol. 2017; 14: 1007-1017Crossref PubMed Scopus (79) Google Scholar Specifically, EcircRNAs have been indicated to be much more steady than linear RNAs in plasma13Koh W. Pan W. Gawad C. Fan H.C. Kerchner G.A. Wyss-Coray T. Blumenfeld Y.J. El-Sayed Y.Y. Quake S.R. Noninvasive in vivo monitoring of tissue-specific global gene expression in humans.Proc. Natl. Acad. Sci. USA. 2014; 111: 7361-7366Crossref PubMed Scopus (200) Google Scholar and saliva,14Bahn J.H. Zhang Q. Li F. Chan T.M. Lin X. Kim Y. Wong D.T. Xiao X. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva.Clin. Chem. 2015; 61: 221-230Crossref PubMed Scopus (489) Google Scholar suggesting that they may be diagnostic biomarkers. In contrast to EcircRNAs, intron-derived circRNAs (IciRNAs) have 3′∼5′ head-to-tail junction regions and differ in stability, subcellular localization, abundance, preservation, and function. IciRNAs are circularized on the chain of the branchpoints 2′∼5′, degenerating from the 3′ end to the branchpoint and avoiding detachment and degradation in a specific way; therefore, they are actually stabilized intron lariats.15Lasda E. Parker R. Circular RNAs: diversity of form and function.RNA. 2014; 20: 1829-1842Crossref PubMed Scopus (848) Google Scholar Their synthesis requires an important site: a c-rich site containing 11 nt near the 5′ terminus, with a length of 7 nt, and a base-rich GU splicing site near the RNA-splicing branch site.16Ivanov A. Memczak S. Wyler E. Torti F. Porath H.T. Orejuela M.R. Piechotta M. Levanon E.Y. Landthaler M. Dieterich C. Rajewsky N. Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals.Cell Rep. 2015; 10: 170-177Abstract Full Text Full Text PDF PubMed Scopus (673) Google Scholar Approximately 20% of EIciRNAs retain introns, and the retention of introns in the exons would make the circRNAs in this subclass more unique while retaining the functions of EcircRNAs and IciRNAs. Mainly located in the nucleus, EIciRNAs interact with U1 small nuclear ribonucleoprotein particle (snRNP) to promote the transcription of their parental genes. In the regulation of nuclear gene expression, EIciRNAs enhance the expression of parental genes in cis and emphasize the transcriptional regulation strategy through a specific RNA-RNA interaction between EIciRNAs and U1 small nuclear RNA (snRNA).17Wilusz J.E. Circular RNAs: Unexpected outputs of many protein-coding genes.RNA Biol. 2017; 14: 1007-1017Crossref PubMed Scopus (79) Google Scholar, 18Li Z. Huang C. Bao C. Chen L. Lin M. Wang X. Zhong G. Yu B. Hu W. Dai L. et al.Exon-intron circular RNAs regulate transcription in the nucleus.Nat. Struct. Mol. Biol. 2015; 22: 256-264Crossref PubMed Scopus (1852) Google Scholar The closed structure of circRNAs is highly stable and resistant to enzyme digestion; therefore, it can be preliminarily purified and identified by the following molecular biology methods.19Jeck W.R. Sharpless N.E. Detecting and characterizing circular RNAs.Nat. 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Compared with homologous gene transcription, nucleic acids have fewer circRNA sequences, and their migration rate in weakly cross-linked gels is slower. Therefore, circRNAs can be identified by northern blot analysis.21Tabak H.F. Van der Horst G. Smit J. Winter A.J. Mul Y. Groot Koerkamp M.J. Discrimination between RNA circles, interlocked RNA circles and lariats using two-dimensional polyacrylamide gel electrophoresis.Nucleic Acids Res. 1988; 16: 6597-6605Crossref PubMed Scopus (33) Google Scholar, 22Suzuki H. Tsukahara T. A view of pre-mRNA splicing from RNase R resistant RNAs.Int. J. Mol. Sci. 2014; 15: 9331-9342Crossref PubMed Scopus (314) Google Scholar (3) Fluorescence in situ hybridization can be used to localize circRNAs at the subcellular level, and small interfering RNAs (siRNAs) or antisense oligonucleotides can be used to interfere with circRNA expression to verify the functions of circRNAs.23Li Z. Huang C. Bao C. Chen L. Lin M. Wang X. Zhong G. Yu B. Hu W. 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Researchers have effectively improved the strategies and algorithms for sequencing analysis as follows: (1) assuming different forms of exon rearrangement, a circRNA candidate sequence boundary combination was constructed and then compared with the sequencing data;25Salzman J. Chen R.E. Olsen M.N. Wang P.L. Brown P.O. Cell-type specific features of circular RNA expression.PLoS Genet. 2013; 9: e1003777Crossref PubMed Scopus (1391) Google Scholar (2) sequencing data are directly matched with the genome sequence through different sequence alignment algorithms; and (3) circRNAs can be directly detected from cDNA sequences by designing multiple splice sequences.26Hoffmann S. Otto C. Doose G. Tanzer A. Langenberger D. Christ S. Kunz M. Holdt L.M. Teupser D. Hackermüller J. Stadler P.F. 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Complementary sequence-mediated exon circularization.Cell. 2014; 159: 134-147Abstract Full Text Full Text PDF PubMed Scopus (1222) Google Scholar The CIRI annotation-related algorithm can not only detect circRNAs transcribed from introns or intergenomic regions but also be applied to the sequencing data of annotated or unannotated eukaryotes. Since circRNAs lack a poly(A) structure, the common oligomeric dT enrichment method is ineffective. The Ribo-Zero kit, which is used to eliminate rRNA and RNase R to remove linear RNAs, can effectively enrich circRNAs.20Suzuki H. Zuo Y. Wang J. Zhang M.Q. Malhotra A. Mayeda A. Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing.Nucleic Acids Res. 2006; 34: e63Crossref PubMed Scopus (428) Google Scholar The functions of circRNAs are diverse and include adsorbing miRNAs as sponges, regulating selective splicing or transcription, interacting with RBPs, translating and deriving pseudogenes, and transporting substances and information. The functions of circRNAs are presented in Figure 2. circRNAs contain a common miRNA response element (MRE) that binds to miRNAs and prevents them from interacting with their target mRNAs.30Memczak S. Jens M. Elefsinioti A. Torti F. Krueger J. Rybak A. Maier L. Mackowiak S.D. Gregersen L.H. Munschauer M. et al.Circular RNAs are a large class of animal RNAs with regulatory potency.Nature. 2013; 495: 333-338Crossref PubMed Scopus (5161) Google Scholar, 31Hansen T.B. Jensen T.I. Clausen B.H. Bramsen J.B. Finsen B. Damgaard C.K. Kjems J. Natural RNA circles function as efficient microRNA sponges.Nature. 2013; 495: 384-388Crossref PubMed Scopus (5173) Google Scholar The first proof of circRNAs acting as miRNA sponges was when cerebellar degeneration-related protein 1 antisense (CDR1as) RNA was determined to be related to miRNA to regulate its functions. CDR1as expression can reduce brain volume and hinder its development in the fetal development process of zebrafish embryos, and the injection of miR-7 can restore normal development, indicating that CDR1as may bind with miR-7.31Hansen T.B. Jensen T.I. Clausen B.H. Bramsen J.B. Finsen B. Damgaard C.K. Kjems J. Natural RNA circles function as efficient microRNA sponges.Nature. 2013; 495: 384-388Crossref PubMed Scopus (5173) Google Scholar circHIPK3 from exon 2 of the HIPK3 gene silenced HIPK3 mRNA and significantly inhibited the growth of human cells. Through luciferase screening, circHIPK3 silenced 9 miRNAs through 18 potential binding sites and directly specifically bound to miR-124 to inhibit its activity. However, bioinformatics analysis showed that circRNAs with a large number of miRNA-binding sites do not necessarily have a strong spongy effect, while other circRNAs confirmed this viewpoint.32Guo J.U. Agarwal V. Guo H. Bartel D.P. Expanded identification and characterization of mammalian circular RNAs.Genome Biol. 2014; 15: 409Crossref PubMed Scopus (1134) Google Scholar, 33You X. Vlatkovic I. Babic A. Will T. Epstein I. Tushev G. Akbalik G. Wang M. Glock C. Quedenau C. et al.Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity.Nat. Neurosci. 2015; 18: 603-610Crossref PubMed Scopus (743) Google Scholar Therefore, whether circRNAs act as miRNA sponges is a common phenomenon that remains to be explained. circRNAs are involved in the regulation of variable splicing and transcription. Variable splicing is the process in which pre-mRNAs splice different mRNA isomers through different splicing methods (different splicing sites are selected), and circRNAs can be used for the regulation of variable splicing. For example, circMBL, produced from the second exon of the splice factor MBL (muscleblind), competes with pre-mRNA. circMbl and its side introns contain conserved MBL-binding sites, which are strongly and specifically inhibited by MBL. The regulation of the MBL level obviously influences the cyclization of circMbl, which is based on the MBL-binding sites in the intron sequence of the flanks.6Qu S. Yang X. Li X. Wang J. Gao Y. Shang R. Sun W. Dou K. Li H. Circular RNA: A new star of noncoding RNAs.Cancer Lett. 2015; 365: 141-148Crossref PubMed Scopus (1222) Google Scholar, 7Ashwal-Fluss R. Meyer M. Pamudurti N.R. Ivanov A. Bartok O. Hanan M. Evantal N. Memczak S. Rajewsky N. Kadener S. circRNA biogenesis competes with pre-mRNA splicing.Mol. Cell. 2014; 56: 55-66Abstract Full Text Full Text PDF PubMed Scopus (1951) Google Scholar In addition, many other circRNAs contain translation initiation sites that potentially compete with their host gene pre-mRNA splices. This mode of regulation can balance the expression levels of circRNAs and the corresponding mRNAs. EIciRNAs can regulate protein production by regulating gene expression at the transcriptional or posttranscriptional level. For example, c-sirt7 can interact with the pol complex, leading to decreased expression of the related anchor protein repeat domain-52 or deacetylase-7. EIciRNAs, mostly localized in the nucleus, can interact with small ribosome U1 snRNP and then bind with pol to promote the transcription of parental genes.18Li Z. Huang C. Bao C. Chen L. Lin M. Wang X. Zhong G. Yu B. Hu W. Dai L. et al.Exon-intron circular RNAs regulate transcription in the nucleus.Nat. Struct. Mol. Biol. 2015; 22: 256-264Crossref PubMed Scopus (1852) Google Scholar circRNAs, like some linear noncoding RNAs, may bind to RBPs to perform biological functions.34Yin Q.F. Yang L. Zhang Y. Xiang J.F. Wu Y.W. Carmichael G.G. Chen L.L. Long noncoding RNAs with snoRNA ends.Mol. Cell. 2012; 48: 219-230Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar, 35Li R. Fox A.H. SPArking Interest in the Long Noncoding RNA World: A New Class of 5′ SnoRNA-Stabilized LncRNA that Influences Alternative Splicing.Mol. Cell. 2016; 64: 435-437Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar When combined with RBPs and ribonucleoprotein complexes, they act as sponges for RBPs, store them,7Ashwal-Fluss R. Meyer M. Pamudurti N.R. Ivanov A. Bartok O. Hanan M. Evantal N. Memczak S. Rajewsky N. Kadener S. circRNA biogenesis competes with pre-mRNA splicing.Mol. Cell. 2014; 56: 55-66Abstract Full Text Full Text PDF PubMed Scopus (1951) Google Scholar and then form complexes. EcircRNAs can bind stably and specifically to some protein molecules in cells. As a scaffold for binding RNA or DNA to complementary sequences, EcircRNAs provide an interaction platform for RBPs, RNA, and DNA. For example, CDR1as can bind to the miRNA action factor Ago2 protein to play a role in protein hydrolysis.36Hansen T.B. Wiklund E.D. Bramsen J.B. Villadsen S.B. Statham A.L. Clark S.J. Kjems J. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA.EMBO J. 2011; 30: 4414-4422Crossref PubMed Scopus (702) Google Scholar Du et al.37Du W.W. Yang W. Liu E. Yang Z. Dhaliwal P. Yang B.B. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2.Nucleic Acids Res. 2016; 44: 2846-2858Crossref PubMed Scopus (1079) Google Scholar found that circ-foxo3 can inhibit cell cycle progression by binding to cyclin-dependent kinase 2 (CDK2) and the cyclin-dependent kinase inhibitor p21. Abdelmohsen et al.38Abdelmohsen K. Panda A.C. Munk R. Grammatikakis I. Dudekula D.B. De S. Kim J. Noh J.H. Kim K.M. Martindale J.L. Gorospe M. Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1.RNA Biol. 2017; 14: 361-369Crossref PubMed Scopus (508) Google Scholar found that circ-PABPN1 could competitively inhibit the binding of the RBP HuR to poly(A)-binding protein nuclear 1 (PABPN1) mRNA, thus reducing the translation level of PABPN1 mRNA. Variable splicing of RNA plays a major part in the occurrence of cancer, and cell proliferation is one of the main characteristics of cancer cells. By studying the role of RBP sponges on circRNAs, the biological function of circRNAs can be better understood, and new clues can be provided for the study of the role of circRNAs in tumorigenesis. As a species of noncoding RNAs, circRNAs basically do not encode proteins. However, if an internal ribosome entry point (IRES) is inserted upstream of the start codon of circRNAs, some circRNAs can also encode proteins that are functionally different from their linear transcripts. As previously shown in vivo and in vitro, an engineered circRNA including an IRES, eukaryotic ribosome 40S subunit, can bind to the circRNA on the IRES to start translation.39Wang Y. Wang Z. Efficient backsplicing produces translatable circular mRNAs.RNA. 2015; 21: 172-179Crossref PubMed Scopus (460) Google Scholar, 40Thomas L.F. Sætrom P. Circular RNAs are depleted of polymorphisms at microRNA binding sites.Bioinformatics. 2014; 30: 2243-2246Crossref PubMed Scopus (148) Google Scholar Similarly, in Escherichia coli, circRNAs with open reading frames of GFP can be transfected to express GFP.39Wang Y. Wang Z. Efficient backsplicing produces translatable circular mRNAs.RNA. 2015; 21: 172-179Crossref PubMed Scopus (460) Google Scholar Du et al.41Du W.W. Zhang C. Yang W. Yong T. Awan F.M. Yang B.B. Identifying and Characterizing circRNA-Protein Interaction.Theranostics. 2017; 7: 4183-4191Crossref PubMed Scopus (380) Google Scholar proved for the first time that circRNAs are modified by m6A; that is, a methyl group is added to the sixth element of the base of the RNA molecule, and the modified circRNAs can be used for protein translation. Zhou et al.42Zhou C. Molinie B. Daneshvar K. Pondick J.V. Wang J. Van Wittenberghe N. Xing Y. Giallourakis C.C. Mullen A.C. Genome-Wide Maps of m6A circRNAs Identify Widespread and Cell-Type-Specific Methylation Patterns that Are Distinct from mRNAs.Cell Rep. 2017; 20: 2262-2276Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar also found that the m6A modification of circRNA showed cell specificity. Legnini et al.43Legnini I. Di Timoteo G. Rossi F. Morlando M. Briganti F. Sthandier O. Fatica A. Santini T. Andronache A. 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