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The Use of circRNAs as Biomarkers of Cancer

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Long Non-Coding RNAs in Cancer

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2348))

Abstract

CircRNAs are a subclass of lncRNAs that have been found to be abundantly present in a wide range of species, including humans. CircRNAs are generally produced by a noncanonical splicing event called backsplicing that is dependent on the canonical splicing machinery, giving rise to circRNAs classified into three main categories: exonic circRNA, circular intronic RNA, and exon–intron circular RNA. Notably, circRNAs possess functional importance and display their functions through different mechanisms of action including sponging miRNAs, or even being translated into functional proteins. In addition, circRNAs also have great potential as biomarkers, particularly in cancer, thanks to their high stability, tissue type and developmental stage specificity, and their presence in biological fluids, which make them promising candidates as noninvasive biomarkers. In this chapter, we describe the most commonly used techniques for the study of circRNAs as cancer biomarkers, including high-throughput techniques such as RNA-Seq and microarrays, and other methods to analyze the presence of specific circRNAs in patient samples.

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References

  1. Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, Kuehn MS, Taylor CM, Neph S, Koch CM, Asthana S, Malhotra A, Adzhubei I, Greenbaum JA, Andrews RM, Flicek P, Boyle PJ, Cao H, Carter NP, Clelland GK, Davis S, Day N, Dhami P, Dillon SC, Dorschner MO, Fiegler H, Giresi PG, Goldy J, Hawrylycz M, Haydock A, Humbert R, James KD, Johnson BE, Johnson EM, Frum TT, Rosenzweig ER, Karnani N, Lee K, Lefebvre GC, Navas PA, Neri F, Parker SC, Sabo PJ, Sandstrom R, Shafer A, Vetrie D, Weaver M, Wilcox S, Yu M, Collins FS, Dekker J, Lieb JD, Tullius TD, Crawford GE, Sunyaev S, Noble WS, Dunham I, Denoeud F, Reymond A, Kapranov P, Rozowsky J, Zheng D, Castelo R, Frankish A, Harrow J, Ghosh S, Sandelin A, Hofacker IL, Baertsch R, Keefe D, Dike S, Cheng J, Hirsch HA, Sekinger EA, Lagarde J, Abril JF, Shahab A, Flamm C, Fried C, Hackermüller J, Hertel J, Lindemeyer M, Missal K, Tanzer A, Washietl S, Korbel J, Emanuelsson O, Pedersen JS, Holroyd N, Taylor R, Swarbreck D, Matthews N, Dickson MC, Thomas DJ, Weirauch MT, Gilbert J, Drenkow J, Bell I, Zhao X, Srinivasan KG, Sung WK, Ooi HS, Chiu KP, Foissac S, Alioto T, Brent M, Pachter L, Tress ML, Valencia A, Choo SW, Choo CY, Ucla C, Manzano C, Wyss C, Cheung E, Clark TG, Brown JB, Ganesh M, Patel S, Tammana H, Chrast J, Henrichsen CN, Kai C, Kawai J, Nagalakshmi U, Wu J, Lian Z, Lian J, Newburger P, Zhang X, Bickel P, Mattick JS, Carninci P, Hayashizaki Y, Weissman S, Hubbard T, Myers RM, Rogers J, Stadler PF, Lowe TM, Wei CL, Ruan Y, Struhl K, Gerstein M, Antonarakis SE, Fu Y, Green ED, Karaöz U, Siepel A, Taylor J, Liefer LA, Wetterstrand KA, Good PJ, Feingold EA, Guyer MS, Cooper GM, Asimenos G, Dewey CN, Hou M, Nikolaev S, Montoya-Burgos JI, Löytynoja A, Whelan S, Pardi F, Massingham T, Huang H, Zhang NR, Holmes I, Mullikin JC, Ureta-Vidal A, Paten B, Seringhaus M, Church D, Rosenbloom K, Kent WJ, Stone EA, Batzoglou S, Goldman N, Hardison RC, Haussler D, Miller W, Sidow A, Trinklein ND, Zhang ZD, Barrera L, Stuart R, King DC, Ameur A, Enroth S, Bieda MC, Kim J, Bhinge AA, Jiang N, Liu J, Yao F, Vega VB, Lee CW, Ng P, Shahab A, Yang A, Moqtaderi Z, Zhu Z, Xu X, Squazzo S, Oberley MJ, Inman D, Singer MA, Richmond TA, Munn KJ, Rada-Iglesias A, Wallerman O, Komorowski J, Fowler JC, Couttet P, Bruce AW, Dovey OM, Ellis PD, Langford CF, Nix DA, Euskirchen G, Hartman S, Urban AE, Kraus P, Van Calcar S, Heintzman N, Kim TH, Wang K, Qu C, Hon G, Luna R, Glass CK, Rosenfeld MG, Aldred SF, Cooper SJ, Halees A, Lin JM, Shulha HP, Zhang X, Xu M, Haidar JN, Yu Y, Ruan Y, Iyer VR, Green RD, Wadelius C, Farnham PJ, Ren B, Harte RA, Hinrichs AS, Trumbower H, Clawson H, Hillman-Jackson J, Zweig AS, Smith K, Thakkapallayil A, Barber G, Kuhn RM, Karolchik D, Armengol L, Bird CP, de Bakker PI, Kern AD, Lopez-Bigas N, Martin JD, Stranger BE, Woodroffe A, Davydov E, Dimas A, Eyras E, Hallgrímsdóttir IB, Huppert J, Zody MC, Abecasis GR, Estivill X, Bouffard GG, Guan X, Hansen NF, Idol JR, Maduro VV, Maskeri B, McDowell JC, Park M, Thomas PJ, Young AC, Blakesley RW, Muzny DM, Sodergren E, Wheeler DA, Worley KC, Jiang H, Weinstock GM, Gibbs RA, Graves T, Fulton R, Mardis ER, Wilson RK, Clamp M, Cuff J, Gnerre S, Jaffe DB, Chang JL, Lindblad-Toh K, Lander ES, Koriabine M, Nefedov M, Osoegawa K, Yoshinaga Y, Zhu B, de Jong PJ (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447(7146):799–816. https://doi.org/10.1038/nature05874

  2. Carninci P, Yasuda J, Hayashizaki Y (2008) Multifaceted mammalian transcriptome. Curr Opin Cell Biol 20(3):274–280. https://doi.org/10.1016/j.ceb.2008.03.008

    Article  CAS  PubMed  Google Scholar 

  3. Pertea M (2012) The human transcriptome: an unfinished story. Genes 3(3):344–360. https://doi.org/10.3390/genes3030344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Palazzo AF, Lee ES (2015) Non-coding RNA: what is functional and what is junk? Front Genet 6:2. https://doi.org/10.3389/fgene.2015.00002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen LL, Yang L (2015) Regulation of circRNA biogenesis. RNA Biol 12(4):381–388. https://doi.org/10.1080/15476286.2015.1020271

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sanger HL, Klotz G, Riesner D, Gross HJ, Kleinschmidt AK (1976) Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci U S A 73(11):3852–3856. https://doi.org/10.1073/pnas.73.11.3852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gross HJ, Domdey H, Lossow C, Jank P, Raba M, Alberty H, Sanger HL (1978) Nucleotide sequence and secondary structure of potato spindle tuber viroid. Nature 273(5659):203–208

    Article  CAS  PubMed  Google Scholar 

  8. Kos A, Dijkema R, Arnberg AC, van der Meide PH, Schellekens H (1986) The hepatitis delta (delta) virus possesses a circular RNA. Nature 323(6088):558–560. https://doi.org/10.1038/323558a0

    Article  CAS  PubMed  Google Scholar 

  9. Nigro JM, Cho KR, Fearon ER, Kern SE, Ruppert JM, Oliner JD, Kinzler KW, Vogelstein B (1991) Scrambled exons. Cell 64(3):607–613

    Article  CAS  PubMed  Google Scholar 

  10. Cocquerelle C, Daubersies P, Majerus MA, Kerckaert JP, Bailleul B (1992) Splicing with inverted order of exons occurs proximal to large introns. EMBO J 11(3):1095–1098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Capel B, Swain A, Nicolis S, Hacker A, Walter M, Koopman P, Goodfellow P, Lovell-Badge R (1993) Circular transcripts of the testis-determining gene Sry in adult mouse testis. Cell 73(5):1019–1030

    Article  CAS  PubMed  Google Scholar 

  12. Zaphiropoulos PG (1996) Circular RNAs from transcripts of the rat cytochrome P450 2C24 gene: correlation with exon skipping. Proc Natl Acad Sci U S A 93(13):6536–6541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zaphiropoulos PG (1997) Exon skipping and circular RNA formation in transcripts of the human cytochrome P-450 2C18 gene in epidermis and of the rat androgen binding protein gene in testis. Mol Cell Biol 17(6):2985–2993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Li XF, Lytton J (1999) A circularized sodium-calcium exchanger exon 2 transcript. J Biol Chem 274(12):8153–8160

    Article  CAS  PubMed  Google Scholar 

  15. Surono A, Van Khanh T, Takeshima Y, Wada H, Yagi M, Takagi M, Koizumi M, Matsuo M (2004) Chimeric RNA/ethylene-bridged nucleic acids promote dystrophin expression in myocytes of duchenne muscular dystrophy by inducing skipping of the nonsense mutation-encoding exon. Hum Gene Ther 15(8):749–757. https://doi.org/10.1089/1043034041648444

    Article  CAS  PubMed  Google Scholar 

  16. Houseley JM, Garcia-Casado Z, Pascual M, Paricio N, O’Dell KM, Monckton DG, Artero RD (2006) Noncanonical RNAs from transcripts of the Drosophila muscleblind gene. J Hered 97(3):253–260. https://doi.org/10.1093/jhered/esj037

    Article  CAS  PubMed  Google Scholar 

  17. Wu W, Ji P, Zhao F (2020) CircAtlas: an integrated resource of one million highly accurate circular RNAs from 1070 vertebrate transcriptomes. Genome Biol 21(1):101. https://doi.org/10.1186/s13059-020-02018-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO (2012) Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PloS One 7(2):e30733. https://doi.org/10.1371/journal.pone.0030733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF, Sharpless NE (2013) Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19(2):141–157. https://doi.org/10.1261/rna.035667.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rybak-Wolf A, Stottmeister C, Glazar P, Jens M, Pino N, Giusti S, Hanan M, Behm M, Bartok O, Ashwal-Fluss R, Herzog M, Schreyer L, Papavasileiou P, Ivanov A, Ohman M, Refojo D, Kadener S, Rajewsky N (2015) Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell 58(5):870–885. https://doi.org/10.1016/j.molcel.2015.03.027

    Article  CAS  PubMed  Google Scholar 

  21. Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495(7441):333–338. https://doi.org/10.1038/nature11928

    Article  CAS  PubMed  Google Scholar 

  22. Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO (2013) Cell-type specific features of circular RNA expression. PLoS Genet 9(9):e1003777. https://doi.org/10.1371/journal.pgen.1003777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Talhouarne GJS, Gall JG (2018) Lariat intronic RNAs in the cytoplasm of vertebrate cells. Proc Natl Acad Sci U S A 115(34):E7970–E7977. https://doi.org/10.1073/pnas.1808816115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang Y, Zhang XO, Chen T, Xiang JF, Yin QF, Xing YH, Zhu S, Yang L, Chen LL (2013) Circular intronic long noncoding RNAs. Mol Cell 51(6):792–806. https://doi.org/10.1016/j.molcel.2013.08.017

    Article  CAS  PubMed  Google Scholar 

  25. Meng X, Li X, Zhang P, Wang J, Zhou Y, Chen M (2017) Circular RNA: an emerging key player in RNA world. Brief Bioinform 18(4):547–557. https://doi.org/10.1093/bib/bbw045

    Article  CAS  PubMed  Google Scholar 

  26. Jeck WR, Sharpless NE (2014) Detecting and characterizing circular RNAs. Nat Biotechnol 32(5):453–461. https://doi.org/10.1038/nbt.2890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, Zhong G, Yu B, Hu W, Dai L, Zhu P, Chang Z, Wu Q, Zhao Y, Jia Y, Xu P, Liu H, Shan G (2015) Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol 22(3):256–264. https://doi.org/10.1038/nsmb.2959

    Article  CAS  PubMed  Google Scholar 

  28. Huang C, Liang D, Tatomer DC, Wilusz JE (2018) A length-dependent evolutionarily conserved pathway controls nuclear export of circular RNAs. Genes Dev 32(9-10):639–644. https://doi.org/10.1101/gad.314856.118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huang G, Li S, Yang N, Zou Y, Zheng D, Xiao T (2017) Recent progress in circular RNAs in human cancers. Cancer Lett 404:8–18. https://doi.org/10.1016/j.canlet.2017.07.002

    Article  CAS  PubMed  Google Scholar 

  30. Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, Evantal N, Memczak S, Rajewsky N, Kadener S (2014) circRNA biogenesis competes with pre-mRNA splicing. Mol Cell 56(1):55–66. https://doi.org/10.1016/j.molcel.2014.08.019

    Article  CAS  PubMed  Google Scholar 

  31. Zhang XO, Wang HB, Zhang Y, Lu X, Chen LL, Yang L (2014) Complementary sequence-mediated exon circularization. Cell 159(1):134–147. https://doi.org/10.1016/j.cell.2014.09.001

    Article  CAS  PubMed  Google Scholar 

  32. Kramer MC, Liang D, Tatomer DC, Gold B, March ZM, Cherry S, Wilusz JE (2015) Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins. Genes Dev 29(20):2168–2182. https://doi.org/10.1101/gad.270421.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, Roslan S, Schreiber AW, Gregory PA, Goodall GJ (2015) The RNA binding protein quaking regulates formation of circRNAs. Cell 160(6):1125–1134. https://doi.org/10.1016/j.cell.2015.02.014

    Article  CAS  PubMed  Google Scholar 

  34. Errichelli L, Dini Modigliani S, Laneve P, Colantoni A, Legnini I, Capauto D, Rosa A, De Santis R, Scarfo R, Peruzzi G, Lu L, Caffarelli E, Shneider NA, Morlando M, Bozzoni I (2017) FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons. Nat Commun 8:14741. https://doi.org/10.1038/ncomms14741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li X, Liu CX, Xue W, Zhang Y, Jiang S, Yin QF, Wei J, Yao RW, Yang L, Chen LL (2017) Coordinated circRNA biogenesis and function with NF90/NF110 in viral infection. Mol Cell 67(2):214–227. e217. https://doi.org/10.1016/j.molcel.2017.05.023

    Article  CAS  PubMed  Google Scholar 

  36. Liang WW, Cheng SC (2015) A novel mechanism for Prp5 function in prespliceosome formation and proofreading the branch site sequence. Genes Dev 29(1):81–93. https://doi.org/10.1101/gad.253708.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ivanov A, Memczak S, Wyler E, Torti F, Porath HT, Orejuela MR, Piechotta M, Levanon EY, Landthaler M, Dieterich C, Rajewsky N (2015) Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep 10(2):170–177. https://doi.org/10.1016/j.celrep.2014.12.019

    Article  CAS  PubMed  Google Scholar 

  38. Aktas T, Avsar Ilik I, Maticzka D, Bhardwaj V, Pessoa Rodrigues C, Mittler G, Manke T, Backofen R, Akhtar A (2017) DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome. Nature 544(7648):115–119. https://doi.org/10.1038/nature21715

    Article  CAS  PubMed  Google Scholar 

  39. Fei T, Chen Y, Xiao T, Li W, Cato L, Zhang P, Cotter MB, Bowden M, Lis RT, Zhao SG, Wu Q, Feng FY, Loda M, He HH, Liu XS, Brown M (2017) Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proc Natl Acad Sci U S A 114(26):E5207–E5215. https://doi.org/10.1073/pnas.1617467114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Stagsted LV, Nielsen KM, Daugaard I, Hansen TB (2019) Noncoding AUG circRNAs constitute an abundant and conserved subclass of circles. Life Sci Alliance 2(3):e201900398. https://doi.org/10.26508/lsa.201900398

    Article  PubMed  PubMed Central  Google Scholar 

  41. Guo JU, Agarwal V, Guo H, Bartel DP (2014) Expanded identification and characterization of mammalian circular RNAs. Genome Biol 15(7):409. https://doi.org/10.1186/s13059-014-0409-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495(7441):384–388. https://doi.org/10.1038/nature11993

    Article  CAS  PubMed  Google Scholar 

  43. Legnini I, Di Timoteo G, Rossi F, Morlando M, Briganti F, Sthandier O, Fatica A, Santini T, Andronache A, Wade M, Laneve P, Rajewsky N, Bozzoni I (2017) Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol Cell 66(1):22–37. e29. https://doi.org/10.1016/j.molcel.2017.02.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang Y, Fan X, Mao M, Song X, Wu P, Zhang Y, Jin Y, Yang Y, Chen LL, Wang Y, Wong CC, Xiao X, Wang Z (2017) Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Res 27(5):626–641. https://doi.org/10.1038/cr.2017.31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang Y, Gao X, Zhang M, Yan S, Sun C, Xiao F, Huang N, Yang X, Zhao K, Zhou H, Huang S, Xie B, Zhang N (2018) Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis. J Natl Cancer Inst 110(3). https://doi.org/10.1093/jnci/djx166

  46. You X, Vlatkovic I, Babic A, Will T, Epstein I, Tushev G, Akbalik G, Wang M, Glock C, Quedenau C, Wang X, Hou J, Liu H, Sun W, Sambandan S, Chen T, Schuman EM, Chen W (2015) Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci 18(4):603–610. https://doi.org/10.1038/nn.3975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zheng Q, Bao C, Guo W, Li S, Chen J, Chen B, Luo Y, Lyu D, Li Y, Shi G, Liang L, Gu J, He X, Huang S (2016) Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun 7:11215. https://doi.org/10.1038/ncomms11215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bak RO, Mikkelsen JG (2014) miRNA sponges: soaking up miRNAs for regulation of gene expression. Wiley Interdiscip Rev RNA 5(3):317–333. https://doi.org/10.1002/wrna.1213

    Article  CAS  PubMed  Google Scholar 

  49. Zhu X, Shao P, Tang Y, Shu M, Hu WW, Zhang Y (2019) hsa_circRNA_100533 regulates GNAS by sponging hsa_miR_933 to prevent oral squamous cell carcinoma. J Cell Biochem 120(11):19159–19171. https://doi.org/10.1002/jcb.29245

    Article  CAS  PubMed  Google Scholar 

  50. Xu H, Sun Y, You B, Huang CP, Ye D, Chang C (2020) Androgen receptor reverses the oncometabolite R-2-hydroxyglutarate-induced prostate cancer cell invasion via suppressing the circRNA-51217/miRNA-646/TGFβ1/p-Smad2/3 signaling. Cancer Lett 472:151–164. https://doi.org/10.1016/j.canlet.2019.12.014

    Article  CAS  PubMed  Google Scholar 

  51. Xiang Q, Kang L, Wang J, Liao Z, Song Y, Zhao K, Wang K, Yang C, Zhang Y (2020) CircRNA-CIDN mitigated compression loading-induced damage in human nucleus pulposus cells via miR-34a-5p/SIRT1 axis. EBioMedicine 53:102679. https://doi.org/10.1016/j.ebiom.2020.102679

    Article  PubMed  PubMed Central  Google Scholar 

  52. Lu J, Wang YH, Yoon C, Huang XY, Xu Y, Xie JW, Wang JB, Lin JX, Chen QY, Cao LL, Zheng CH, Li P, Huang CM (2020) Circular RNA circ-RanGAP1 regulates VEGFA expression by targeting miR-877-3p to facilitate gastric cancer invasion and metastasis. Cancer Lett 471:38–48. https://doi.org/10.1016/j.canlet.2019.11.038

    Article  CAS  PubMed  Google Scholar 

  53. Kong Z, Wan X, Lu Y, Zhang Y, Huang Y, Xu Y, Liu Y, Zhao P, Xiang X, Li L, Li Y (2020) Circular RNA circFOXO3 promotes prostate cancer progression through sponging miR-29a-3p. J Cell Mol Med 24(1):799–813. https://doi.org/10.1111/jcmm.14791

    Article  CAS  PubMed  Google Scholar 

  54. Ragan C, Goodall GJ, Shirokikh NE, Preiss T (2019) Insights into the biogenesis and potential functions of exonic circular RNA. Sci Rep 9(1):2048. https://doi.org/10.1038/s41598-018-37037-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kelly S, Greenman C, Cook PR, Papantonis A (2015) Exon Skipping Is Correlated with Exon Circularization. Journal of molecular biology 427(15):2414–2417. https://doi.org/10.1016/j.jmb.2015.02.018

    Article  CAS  PubMed  Google Scholar 

  56. Qu S, Yang X, Li X, Wang J, Gao Y, Shang R, Sun W, Dou K, Li H (2015) Circular RNA: a new star of noncoding RNAs. Cancer Lett 365(2):141–148. https://doi.org/10.1016/j.canlet.2015.06.003

    Article  CAS  PubMed  Google Scholar 

  57. Chao CW, Chan DC, Kuo A, Leder P (1998) The mouse formin (Fmn) gene: abundant circular RNA transcripts and gene-targeted deletion analysis. Mol Med 4(9):614–628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Moehle EA, Braberg H, Krogan NJ, Guthrie C (2014) Adventures in time and space: splicing efficiency and RNA polymerase II elongation rate. RNA Biol 11(4):313–319. https://doi.org/10.4161/rna.28646

    Article  PubMed  PubMed Central  Google Scholar 

  59. Zhang Y, Xue W, Li X, Zhang J, Chen S, Zhang JL, Yang L, Chen LL (2016) The Biogenesis of Nascent Circular RNAs. Cell reports 15(3):611–624. https://doi.org/10.1016/j.celrep.2016.03.058

    Article  CAS  PubMed  Google Scholar 

  60. Huang A, Zheng H, Wu Z, Chen M, Huang Y (2020) Circular RNA-protein interactions: functions, mechanisms, and identification. Theranostics 10(8):3503–3517. https://doi.org/10.7150/thno.42174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gualandi F, Trabanelli C, Rimessi P, Calzolari E, Toffolatti L, Patarnello T, Kunz G, Muntoni F, Ferlini A (2003) Multiple exon skipping and RNA circularisation contribute to the severe phenotypic expression of exon 5 dystrophin deletion. J Med Genet 40(8):e100. https://doi.org/10.1136/jmg.40.8.e100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen LL (2016) The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol 17(4):205–211. https://doi.org/10.1038/nrm.2015.32

    Article  CAS  PubMed  Google Scholar 

  63. Fan X, Weng X, Zhao Y, Chen W, Gan T, Xu D (2017) Circular RNAs in cardiovascular disease: an overview. Biomed Res Int 2017:5135781. https://doi.org/10.1155/2017/5135781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ma N, Tie C, Yu B, Zhang W, Wan J (2020) Circular RNAs regulate its parental genes transcription in the AD mouse model using two methods of library construction. FASEB J 34(8):10342–10356. https://doi.org/10.1096/fj.201903157R

    Article  CAS  PubMed  Google Scholar 

  65. Chen N, Zhao G, Yan X, Lv Z, Yin H, Zhang S, Song W, Li X, Li L, Du Z, Jia L, Zhou L, Li W, Hoffman AR, Hu JF, Cui J (2018) A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1. Genome Biol 19(1):218. https://doi.org/10.1186/s13059-018-1594-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Du WW, Zhang C, Yang W, Yong T, Awan FM, Yang BB (2017) Identifying and characterizing circRNA-protein interaction. Theranostics 7(17):4183–4191. https://doi.org/10.7150/thno.21299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Aufiero S, Reckman YJ, Pinto YM, Creemers EE (2019) Circular RNAs open a new chapter in cardiovascular biology. Nat Rev Cardiol 16(8):503–514. https://doi.org/10.1038/s41569-019-0185-2

    Article  PubMed  Google Scholar 

  68. Du WW, Yang W, Chen Y, Wu ZK, Foster FS, Yang Z, Li X, Yang BB (2017) Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses. Eur Heart J 38(18):1402–1412. https://doi.org/10.1093/eurheartj/ehw001

    Article  CAS  PubMed  Google Scholar 

  69. Hansen TB, Wiklund ED, Bramsen JB, Villadsen SB, Statham AL, Clark SJ, Kjems J (2011) miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J 30(21):4414–4422. https://doi.org/10.1038/emboj.2011.359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Holdt LM, Stahringer A, Sass K, Pichler G, Kulak NA, Wilfert W, Kohlmaier A, Herbst A, Northoff BH, Nicolaou A, Gabel G, Beutner F, Scholz M, Thiery J, Musunuru K, Krohn K, Mann M, Teupser D (2016) Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nat Commun 7:12429. https://doi.org/10.1038/ncomms12429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Abdelmohsen K, Panda AC, Munk R, Grammatikakis I, Dudekula DB, De S, Kim J, Noh JH, Kim KM, Martindale JL, Gorospe M (2017) Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1. RNA Biol 14(3):361–369. https://doi.org/10.1080/15476286.2017.1279788

    Article  PubMed  PubMed Central  Google Scholar 

  72. Yu CY, Kuo HC (2019) The emerging roles and functions of circular RNAs and their generation. J Biomed Sci 26(1):29. https://doi.org/10.1186/s12929-019-0523-z

    Article  PubMed  PubMed Central  Google Scholar 

  73. Zeng Y, Du WW, Wu Y, Yang Z, Awan FM, Li X, Yang W, Zhang C, Yang Q, Yee A, Chen Y, Yang F, Sun H, Huang R, Yee AJ, Li RK, Wu Z, Backx PH, Yang BB (2017) A circular RNA binds to and activates AKT phosphorylation and nuclear localization reducing apoptosis and enhancing cardiac repair. Theranostics 7(16):3842–3855. https://doi.org/10.7150/thno.19764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yang ZG, Awan FM, Du WW, Zeng Y, Lyu J, Wu GS, Yang W, Yang BB (2017) The circular RNA interacts with STAT3, increasing its nuclear translocation and wound repair by modulating Dnmt3a and miR-17 function. Mol Ther 25(9):2062–2074. https://doi.org/10.1016/j.ymthe.2017.05.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Du WW, Yang W, Li X, Awan FM, Yang Z, Fang L, Lyu J, Li F, Peng C, Krylov SN, Xie Y, Zhang Y, He C, Wu N, Zhang C, Sdiri M, Dong J, Ma J, Gao C, Hibberd S, Yang BB (2018) A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy. Oncogene 37(44):5829–5842. https://doi.org/10.1038/s41388-018-0369-y

    Article  CAS  PubMed  Google Scholar 

  76. Sun YM, Wang WT, Zeng ZC, Chen TQ, Han C, Pan Q, Huang W, Fang K, Sun LY, Zhou YF, Luo XQ, Luo C, Du X, Chen YQ (2019) circMYBL2, a circRNA from MYBL2, regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression. Blood 134(18):1533–1546. https://doi.org/10.1182/blood.2019000802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang S, Zhang Y, Cai Q, Ma M, Jin LY, Weng M, Zhou D, Tang Z, Wang JD, Quan Z (2019) Circular RNA FOXP1 promotes tumor progression and Warburg effect in gallbladder cancer by regulating PKLR expression. Mol Cancer 18(1):145. https://doi.org/10.1186/s12943-019-1078-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Garikipati VNS, Verma SK, Cheng Z, Liang D, Truongcao MM, Cimini M, Yue Y, Huang G, Wang C, Benedict C, Tang Y, Mallaredy V, Ibetti J, Grisanti L, Schumacher SM, Gao E, Rajan S, Wilusz JE, Goukassian D, Houser SR, Koch WJ, Kishore R (2019) Circular RNA CircFndc3b modulates cardiac repair after myocardial infarction via FUS/VEGF-A axis. Nat Commun 10(1):4317. https://doi.org/10.1038/s41467-019-11777-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fang L, Du WW, Awan FM, Dong J, Yang BB (2019) The circular RNA circ-Ccnb1 dissociates Ccnb1/Cdk1 complex suppressing cell invasion and tumorigenesis. Cancer Lett 459:216–226. https://doi.org/10.1016/j.canlet.2019.05.036

    Article  CAS  PubMed  Google Scholar 

  80. Huang X, He M, Huang S, Lin R, Zhan M, Yang D, Shen H, Xu S, Cheng W, Yu J, Qiu Z, Wang J (2019) Circular RNA circERBB2 promotes gallbladder cancer progression by regulating PA2G4-dependent rDNA transcription. Mol Cancer 18(1):166. https://doi.org/10.1186/s12943-019-1098-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Li H, Yang F, Hu A, Wang X, Fang E, Chen Y, Li D, Song H, Wang J, Guo Y, Liu Y, Li H, Huang K, Zheng L, Tong Q (2019) Therapeutic targeting of circ-CUX1/EWSR1/MAZ axis inhibits glycolysis and neuroblastoma progression. EMBO Mol Med 11(12):e10835. https://doi.org/10.15252/emmm.201910835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hu X, Wu D, He X, Zhao H, He Z, Lin J, Wang K, Wang W, Pan Z, Lin H, Wang M (2019) circGSK3β promotes metastasis in esophageal squamous cell carcinoma by augmenting β-catenin signaling. Mol Cancer 18(1):160. https://doi.org/10.1186/s12943-019-1095-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Pandey PR, Yang JH, Tsitsipatis D, Panda AC, Noh JH, Kim KM, Munk R, Nicholson T, Hanniford D, Argibay D, Yang X, Martindale JL, Chang MW, Jones SW, Hernando E, Sen P, De S, Abdelmohsen K, Gorospe M (2020) circSamd4 represses myogenic transcriptional activity of PUR proteins. Nucleic Acids Res 48(7):3789–3805. https://doi.org/10.1093/nar/gkaa035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wong CH, Lou UK, Li Y, Chan SL, Tong JH, To KF, Chen Y (2020) CircFOXK2 promotes growth and metastasis of pancreatic ductal adenocarcinoma by complexing with RNA-binding proteins and sponging MiR-942. Cancer Res 80(11):2138–2149. https://doi.org/10.1158/0008-5472.can-19-3268

    Article  CAS  PubMed  Google Scholar 

  85. Liu Z, Wang Q, Wang X, Xu Z, Wei X, Li J (2020) Circular RNA cIARS regulates ferroptosis in HCC cells through interacting with RNA binding protein ALKBH5. Cell Death Discov 6:72. https://doi.org/10.1038/s41420-020-00306-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gan X, Zhu H, Jiang X, Obiegbusi SC, Yong M, Long X, Hu J (2020) CircMUC16 promotes autophagy of epithelial ovarian cancer via interaction with ATG13 and miR-199a. Mol Cancer 19(1):45. https://doi.org/10.1186/s12943-020-01163-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lou J, Hao Y, Lin K, Lyu Y, Chen M, Wang H, Zou D, Jiang X, Wang R, Jin D, Lam EW, Shao S, Liu Q, Yan J, Wang X, Chen P, Zhang B, Jin B (2020) Circular RNA CDR1as disrupts the p53/MDM2 complex to inhibit Gliomagenesis. Mol Cancer 19(1):138. https://doi.org/10.1186/s12943-020-01253-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chen CY, Sarnow P (1995) Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science 268(5209):415–417

    Article  CAS  PubMed  Google Scholar 

  89. Pamudurti NR, Bartok O, Jens M, Ashwal-Fluss R, Stottmeister C, Ruhe L, Hanan M, Wyler E, Perez-Hernandez D, Ramberger E, Shenzis S, Samson M, Dittmar G, Landthaler M, Chekulaeva M, Rajewsky N, Kadener S (2017) Translation of CircRNAs. Mol Cell 66(1):9–21.e7. https://doi.org/10.1016/j.molcel.2017.02.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Begum S, Yiu A, Stebbing J, Castellano L (2018) Novel tumour suppressive protein encoded by circular RNA, circ-SHPRH, in glioblastomas. Oncogene 37(30):4055–4057. https://doi.org/10.1038/s41388-018-0230-3

    Article  CAS  PubMed  Google Scholar 

  91. Lei M, Zheng G, Ning Q, Zheng J, Dong D (2020) Translation and functional roles of circular RNAs in human cancer. Mol Cancer 19(1):30. https://doi.org/10.1186/s12943-020-1135-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Di Timoteo G, Dattilo D, Centrón-Broco A, Colantoni A, Guarnacci M, Rossi F, Incarnato D, Oliviero S, Fatica A, Morlando M, Bozzoni I (2020) Modulation of circRNA Metabolism by m(6)A modification. Cell Rep 31(6):107641. https://doi.org/10.1016/j.celrep.2020.107641

    Article  CAS  PubMed  Google Scholar 

  93. Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J (2019) The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet 20(11):675–691. https://doi.org/10.1038/s41576-019-0158-7

    Article  CAS  PubMed  Google Scholar 

  94. Zhang M, Zhao K, Xu X, Yang Y, Yan S, Wei P, Liu H, Xu J, Xiao F, Zhou H, Yang X, Huang N, Liu J, He K, Xie K, Zhang G, Huang S, Zhang N (2018) A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun 9(1):4475. https://doi.org/10.1038/s41467-018-06862-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhang M, Huang N, Yang X, Luo J, Yan S, Xiao F, Chen W, Gao X, Zhao K, Zhou H, Li Z, Ming L, Xie B, Zhang N (2018) A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. Oncogene 37(13):1805–1814. https://doi.org/10.1038/s41388-017-0019-9

    Article  CAS  PubMed  Google Scholar 

  96. Liang WC, Wong CW, Liang PP, Shi M, Cao Y, Rao ST, Tsui SK, Waye MM, Zhang Q, Fu WM, Zhang JF (2019) Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol 20(1):84. https://doi.org/10.1186/s13059-019-1685-4

    Article  PubMed  PubMed Central  Google Scholar 

  97. Zheng X, Chen L, Zhou Y, Wang Q, Zheng Z, Xu B, Wu C, Zhou Q, Hu W, Wu C, Jiang J (2019) A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling. Mol Cancer 18(1):47. https://doi.org/10.1186/s12943-019-1010-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Pan Z, Cai J, Lin J, Zhou H, Peng J, Liang J, Xia L, Yin Q, Zou B, Zheng J, Qiao L, Zhang L (2020) A novel protein encoded by circFNDC3B inhibits tumor progression and EMT through regulating Snail in colon cancer. Mol Cancer 19(1):71. https://doi.org/10.1186/s12943-020-01179-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Cocquerelle C, Mascrez B, Hetuin D, Bailleul B (1993) Mis-splicing yields circular RNA molecules. FASEB J 7(1):155–160

    Article  CAS  PubMed  Google Scholar 

  100. Memczak S, Papavasileiou P, Peters O, Rajewsky N (2015) Identification and characterization of circular RNAs as a new class of putative biomarkers in human blood. PLoS One 10(10):e0141214. https://doi.org/10.1371/journal.pone.0141214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, Chen D, Gu J, He X, Huang S (2015) Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res 25(8):981–984. https://doi.org/10.1038/cr.2015.82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhang X, Xu Y, Qian Z, Zheng W, Wu Q, Chen Y, Zhu G, Liu Y, Bian Z, Xu W, Zhang Y, Sun F, Pan Q, Wang J, Du L, Yu Y (2018) circRNA_104075 stimulates YAP-dependent tumorigenesis through the regulation of HNF4a and may serve as a diagnostic marker in hepatocellular carcinoma. Cell Death Dis 9(11):1091. https://doi.org/10.1038/s41419-018-1132-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chen X, Chen RX, Wei WS, Li YH, Feng ZH, Tan L, Chen JW, Yuan GJ, Chen SL, Guo SJ, Xiao KH, Liu ZW, Luo JH, Zhou FJ, Xie D (2018) PRMT5 circular RNA promotes metastasis of urothelial carcinoma of the bladder through sponging miR-30c to induce epithelial-mesenchymal transition. Clin Cancer Res 24(24):6319–6330. https://doi.org/10.1158/1078-0432.ccr-18-1270

    Article  CAS  PubMed  Google Scholar 

  104. Luo YH, Yang YP, Chien CS, Yarmishyn AA, Ishola AA, Chien Y, Chen YM, Huang TW, Lee KY, Huang WC, Tsai PH, Lin TW, Chiou SH, Liu CY, Chang CC, Chen MT, Wang ML (2020) Plasma level of circular RNA hsa_circ_0000190 correlates with tumor progression and poor treatment response in advanced lung cancers. Cancers 12(7):1740. https://doi.org/10.3390/cancers12071740

    Article  CAS  PubMed Central  Google Scholar 

  105. Rong D, Lu C, Zhang B, Fu K, Zhao S, Tang W, Cao H (2019) CircPSMC3 suppresses the proliferation and metastasis of gastric cancer by acting as a competitive endogenous RNA through sponging miR-296-5p. Mol Cancer 18(1):25. https://doi.org/10.1186/s12943-019-0958-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Pan B, Qin J, Liu X, He B, Wang X, Pan Y, Sun H, Xu T, Xu M, Chen X, Xu X, Zeng K, Sun L, Wang S (2019) Identification of serum exosomal hsa-circ-0004771 as a novel diagnostic biomarker of colorectal cancer. Front Genet 10:1096. https://doi.org/10.3389/fgene.2019.01096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Han D, Li J, Wang H, Su X, Hou J, Gu Y, Qian C, Lin Y, Liu X, Huang M, Li N, Zhou W, Yu Y, Cao X (2017) Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology 66(4):1151–1164. https://doi.org/10.1002/hep.29270

    Article  CAS  PubMed  Google Scholar 

  108. Liang G, Liu Z, Tan L, Su AN, Jiang WG, Gong C (2017) HIF1alpha-associated circDENND4C promotes proliferation of breast cancer cells in hypoxic environment. Anticancer Res 37(8):4337–4343. https://doi.org/10.21873/anticanres.11827

    Article  CAS  PubMed  Google Scholar 

  109. Yao Z, Luo J, Hu K, Lin J, Huang H, Wang Q, Zhang P, Xiong Z, He C, Huang Z, Liu B, Yang Y (2017) ZKSCAN1 gene and its related circular RNA (circZKSCAN1) both inhibit hepatocellular carcinoma cell growth, migration, and invasion but through different signaling pathways. Mol Oncol 11(4):422–437. https://doi.org/10.1002/1878-0261.12045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Liang HF, Zhang XZ, Liu BG, Jia GT, Li WL (2017) Circular RNA circ-ABCB10 promotes breast cancer proliferation and progression through sponging miR-1271. Am J Cancer Res 7(7):1566–1576

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Huang XY, Huang ZL, Xu YH, Zheng Q, Chen Z, Song W, Zhou J, Tang ZY, Huang XY (2017) Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-100338/miR-141-3p pathway in hepatitis B-related hepatocellular carcinoma. Sci Rep 7(1):5428. https://doi.org/10.1038/s41598-017-05432-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Liu W, Zhang J, Zou C, Xie X, Wang Y, Wang B, Zhao Z, Tu J, Wang X, Li H, Shen J, Yin J (2017) Microarray expression profile and functional analysis of circular RNAs in osteosarcoma. Cell Physiol Biochem 43(3):969–985. https://doi.org/10.1159/000481650

    Article  CAS  PubMed  Google Scholar 

  113. Huang G, Zhu H, Shi Y, Wu W, Cai H, Chen X (2015) cir-ITCH plays an inhibitory role in colorectal cancer by regulating the Wnt/beta-catenin pathway. PLoS One 10(6):e0131225. https://doi.org/10.1371/journal.pone.0131225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wan L, Zhang L, Fan K, Cheng ZX, Sun QC, Wang JJ (2016) Circular RNA-ITCH suppresses lung cancer proliferation via inhibiting the Wnt/beta-catenin pathway. Biomed Res Int 2016:1579490. https://doi.org/10.1155/2016/1579490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pan H, Li T, Jiang Y, Pan C, Ding Y, Huang Z, Yu H, Kong D (2018) Overexpression of circular RNA ciRS-7 abrogates the tumor suppressive effect of miR-7 on gastric cancer via PTEN/PI3K/AKT signaling pathway. J Cell Biochem 119(1):440–446. https://doi.org/10.1002/jcb.26201

    Article  CAS  PubMed  Google Scholar 

  116. Zhong Z, Lv M, Chen J (2016) Screening differential circular RNA expression profiles reveals the regulatory role of circTCF25-miR-103a-3p/miR-107-CDK6 pathway in bladder carcinoma. Sci Rep 6:30919. https://doi.org/10.1038/srep30919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Barrett SP, Parker KR, Horn C, Mata M, Salzman J (2017) ciRS-7 exonic sequence is embedded in a long non-coding RNA locus. PLoS Genet 13(12):e1007114. https://doi.org/10.1371/journal.pgen.1007114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hanniford D, Ulloa-Morales A, Karz A, Berzoti-Coelho MG, Moubarak RS, Sánchez-Sendra B, Kloetgen A, Davalos V, Imig J, Wu P, Vasudevaraja V, Argibay D, Lilja K, Tabaglio T, Monteagudo C, Guccione E, Tsirigos A, Osman I, Aifantis I, Hernando E (2020) Epigenetic silencing of CDR1as drives IGF2BP3-mediated melanoma invasion and metastasis. Cancer Cell 37(1):55–70.e15. https://doi.org/10.1016/j.ccell.2019.12.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Uhr K, Sieuwerts AM, de Weerd V, Smid M, Hammerl D, Foekens JA, Martens JWM (2018) Association of microRNA-7 and its binding partner CDR1-AS with the prognosis and prediction of 1(st)-line tamoxifen therapy in breast cancer. Sci Rep 8(1):9657. https://doi.org/10.1038/s41598-018-27987-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Yang W, Yang X, Wang X, Gu J, Zhou D, Wang Y, Yin B, Guo J, Zhou M (2019) Silencing CDR1as enhances the sensitivity of breast cancer cells to drug resistance by acting as a miR-7 sponge to down-regulate REGgamma. J Cell Mol Med 23(8):4921–4932. https://doi.org/10.1111/jcmm.14305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhang X, Yang D, Wei Y (2018) Overexpressed CDR1as functions as an oncogene to promote the tumor progression via miR-7 in non-small-cell lung cancer. Onco Targets Ther 11:3979–3987. https://doi.org/10.2147/ott.s158316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Weng W, Wei Q, Toden S, Yoshida K, Nagasaka T, Fujiwara T, Cai S, Qin H, Ma Y, Goel A (2017) Circular RNA ciRS-7-A promising prognostic biomarker and a potential therapeutic target in colorectal cancer. Clin Cancer Res 23(14):3918–3928. https://doi.org/10.1158/1078-0432.ccr-16-2541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Yu L, Gong X, Sun L, Zhou Q, Lu B, Zhu L (2016) The circular RNA Cdr1as act as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. PLoS One 11(7):e0158347. https://doi.org/10.1371/journal.pone.0158347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yang X, Xiong Q, Wu Y, Li S, Ge F (2017) Quantitative proteomics reveals the regulatory networks of circular RNA CDR1as in hepatocellular carcinoma cells. J Proteome Res 16(10):3891–3902. https://doi.org/10.1021/acs.jproteome.7b00519

    Article  CAS  PubMed  Google Scholar 

  125. Zhong Q, Huang J, Wei J, Wu R (2019) Circular RNA CDR1as sponges miR-7-5p to enhance E2F3 stability and promote the growth of nasopharyngeal carcinoma. Cancer Cell Int 19:252. https://doi.org/10.1186/s12935-019-0959-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yang X, Li S, Wu Y, Ge F, Chen Y, Xiong Q (2020) The circular RNA CDR1as regulate cell proliferation via TMED2 and TMED10. BMC Cancer 20(1):312. https://doi.org/10.1186/s12885-020-06794-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Han JY, Guo S, Wei N, Xue R, Li W, Dong G, Li J, Tian X, Chen C, Qiu S, Wang T, Xiao Q, Liu C, Xu J, Chen KS (2020) ciRS-7 promotes the proliferation and migration of papillary thyroid cancer by negatively regulating the miR-7/epidermal growth factor receptor axis. Biomed Res Int 2020:9875636. https://doi.org/10.1155/2020/9875636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Huang H, Wei L, Qin T, Yang N, Li Z, Xu Z (2019) Circular RNA ciRS-7 triggers the migration and invasion of esophageal squamous cell carcinoma via miR-7/KLF4 and NF-κB signals. Cancer Biol Ther 20(1):73–80. https://doi.org/10.1080/15384047.2018.1507254

    Article  CAS  PubMed  Google Scholar 

  129. Li C, Li M, Xue Y (2019) Downregulation of CircRNA CDR1as specifically triggered low-dose Diosbulbin-B induced gastric cancer cell death by regulating miR-7-5p/REGγ axis. Biomed Pharmacother 120:109462. https://doi.org/10.1016/j.biopha.2019.109462

    Article  CAS  PubMed  Google Scholar 

  130. Yang W, Gu J, Wang X, Wang Y, Feng M, Zhou D, Guo J, Zhou M (2019) Inhibition of circular RNA CDR1as increases chemosensitivity of 5-FU-resistant BC cells through up-regulating miR-7. J Cell Mol Med 23(5):3166–3177. https://doi.org/10.1111/jcmm.14171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zou Y, Zheng S, Deng X, Yang A, Kong Y, Kohansal M, Hu X, Xie X (2020) Diagnostic and prognostic value of circular RNA CDR1as/ciRS-7 for solid tumours: a systematic review and meta-analysis. J Cell Mol Med 24(17):9507–9517. https://doi.org/10.1111/jcmm.15619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Tian G, Li G, Guan L, Wang Z, Li N (2020) Prognostic value of circular RNA ciRS-7 in various cancers: a PRISMA-compliant meta-analysis. Biomed Res Int 2020:1487609. https://doi.org/10.1155/2020/1487609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Su C, Han Y, Zhang H, Li Y, Yi L, Wang X, Zhou S, Yu D, Song X, Xiao N, Cao X, Liu Z (2018) CiRS-7 targeting miR-7 modulates the progression of non-small cell lung cancer in a manner dependent on NF-κB signalling. J Cell Mol Med 22(6):3097–3107. https://doi.org/10.1111/jcmm.13587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Tang W, Ji M, He G, Yang L, Niu Z, Jian M, Wei Y, Ren L, Xu J (2017) Silencing CDR1as inhibits colorectal cancer progression through regulating microRNA-7. Onco Targets Ther 10:2045–2056. https://doi.org/10.2147/ott.s131597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhao Z, Ji M, Wang Q, He N, Li Y (2019) Circular RNA Cdr1as upregulates SCAI to suppress cisplatin resistance in ovarian cancer via miR-1270 suppression. Mol Ther Nucleic Acids 18:24–33. https://doi.org/10.1016/j.omtn.2019.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Wenzhe G, Jiahao X, Cheng P, Hongwei Z, Xiao Y (2020) Circular RNA HIPK3 is a prognostic and clinicopathological predictor in malignant tumor patients. J Cancer 11(14):4230–4239. https://doi.org/10.7150/jca.40001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Jin P, Huang Y, Zhu P, Zou Y, Shao T, Wang O (2018) CircRNA circHIPK3 serves as a prognostic marker to promote glioma progression by regulating miR-654/IGF2BP3 signaling. Biochem Biophys Res Commun 503(3):1570–1574. https://doi.org/10.1016/j.bbrc.2018.07.081

    Article  CAS  PubMed  Google Scholar 

  138. Wei J, Xu H, Wei W, Wang Z, Zhang Q, De W, Shu Y (2020) circHIPK3 promotes cell proliferation and migration of gastric cancer by sponging miR-107 and regulating BDNF expression. Onco Targets Ther 13:1613–1624. https://doi.org/10.2147/ott.s226300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Cheng J, Zhuo H, Xu M, Wang L, Xu H, Peng J, Hou J, Lin L, Cai J (2018) Regulatory network of circRNA-miRNA-mRNA contributes to the histological classification and disease progression in gastric cancer. J Transl Med 16(1):216. https://doi.org/10.1186/s12967-018-1582-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Liu Y, Xia L, Dong L, Wang J, Xiao Q, Yu X, Zhu H (2020) CircHIPK3 promotes gemcitabine (GEM) resistance in pancreatic cancer cells by sponging miR-330-5p and targets RASSF1. Cancer Manag Res 12:921–929. https://doi.org/10.2147/cmar.s239326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Liu N, Zhang J, Zhang LY, Wang L (2018) CircHIPK3 is upregulated and predicts a poor prognosis in epithelial ovarian cancer. Eur Rev Med Pharmacol Sci 22(12):3713–3718. https://doi.org/10.26355/eurrev_201806_15250

    Article  CAS  PubMed  Google Scholar 

  142. Zeng K, Chen X, Xu M, Liu X, Hu X, Xu T, Sun H, Pan Y, He B, Wang S (2018) CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7. Cell Death Dis 9(4):417. https://doi.org/10.1038/s41419-018-0454-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Zhang Y, Li C, Liu X, Wang Y, Zhao R, Yang Y, Zheng X, Zhang Y, Zhang X (2019) circHIPK3 promotes oxaliplatin-resistance in colorectal cancer through autophagy by sponging miR-637. EBioMedicine 48:277–288. https://doi.org/10.1016/j.ebiom.2019.09.051

    Article  PubMed  PubMed Central  Google Scholar 

  144. Chen D, Lu X, Yang F, Xing N (2019) Circular RNA circHIPK3 promotes cell proliferation and invasion of prostate cancer by sponging miR-193a-3p and regulating MCL1 expression. Cancer Manag Res 11:1415–1423. https://doi.org/10.2147/cmar.s190669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Li Y, Zheng F, Xiao X, Xie F, Tao D, Huang C, Liu D, Wang M, Wang L, Zeng F, Jiang G (2017) CircHIPK3 sponges miR-558 to suppress heparanase expression in bladder cancer cells. EMBO Rep 18(9):1646–1659. https://doi.org/10.15252/embr.201643581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Xie F, Zhao N, Zhang H, Xie D (2020) Circular RNA CircHIPK3 promotes gemcitabine sensitivity in bladder cancer. J Cancer 11(7):1907–1912. https://doi.org/10.7150/jca.39722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Xiao-Long M, Kun-Peng Z, Chun-Lin Z (2018) Circular RNA circ_HIPK3 is down-regulated and suppresses cell proliferation, migration and invasion in osteosarcoma. J Cancer 9(10):1856–1862. https://doi.org/10.7150/jca.24619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hu J, Wang L, Chen J, Gao H, Zhao W, Huang Y, Jiang T, Zhou J, Chen Y (2018) The circular RNA circ-ITCH suppresses ovarian carcinoma progression through targeting miR-145/RASA1 signaling. Biochem Biophys Res Commun 505(1):222–228. https://doi.org/10.1016/j.bbrc.2018.09.060

    Article  CAS  PubMed  Google Scholar 

  149. Lin C, Xu X, Yang Q, Liang L, Qiao S (2020) Circular RNA ITCH suppresses proliferation, invasion, and glycolysis of ovarian cancer cells by up-regulating CDH1 via sponging miR-106a. Cancer Cell Int 20:336. https://doi.org/10.1186/s12935-020-01420-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Yang C, Yuan W, Yang X, Li P, Wang J, Han J, Tao J, Li P, Yang H, Lv Q, Zhang W (2018) Circular RNA circ-ITCH inhibits bladder cancer progression by sponging miR-17/miR-224 and regulating p21, PTEN expression. Mol Cancer 17(1):19. https://doi.org/10.1186/s12943-018-0771-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Li F, Ma K, Sun M, Shi S (2018) Identification of the tumor-suppressive function of circular RNA ITCH in glioma cells through sponging miR-214 and promoting linear ITCH expression. Am J Transl Res 10(5):1373–1386

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Hao C, Wangzhou K, Liang Z, Liu C, Wang L, Gong L, Tan Y, Li C, Lai Z, Hu G (2020) Circular RNA ITCH suppresses cell proliferation but induces apoptosis in oral squamous cell carcinoma by regulating miR-421/PDCD4 Axis. Cancer Manag Res 12:5651–5658. https://doi.org/10.2147/cmar.s258887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Wang X, Wang R, Wu Z, Bai P (2019) Circular RNA ITCH suppressed prostate cancer progression by increasing HOXB13 expression via spongy miR-17-5p. Cancer Cell Int 19:328. https://doi.org/10.1186/s12935-019-0994-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Wang M, Chen B, Ru Z, Cong L (2018) CircRNA circ-ITCH suppresses papillary thyroid cancer progression through miR-22-3p/CBL/beta-catenin pathway. Biochem Biophys Res Commun 504(1):283–288. https://doi.org/10.1016/j.bbrc.2018.08.175

    Article  CAS  PubMed  Google Scholar 

  155. Zeng W, Liu Y, Li WT, Li Y, Zhu JF (2020) CircFNDC3B sequestrates miR-937-5p to derepress TIMP3 and inhibit colorectal cancer progression. Mol Oncol 14(11):2960–2984. https://doi.org/10.1002/1878-0261.12796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Liu H, Bi J, Dong W, Yang M, Shi J, Jiang N, Lin T, Huang J (2018) Invasion-related circular RNA circFNDC3B inhibits bladder cancer progression through the miR-1178-3p/G3BP2/SRC/FAK axis. Mol Cancer 17(1):161. https://doi.org/10.1186/s12943-018-0908-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Chen T, Yu Q, Shao S, Guo L (2020) Circular RNA circFNDC3B protects renal carcinoma by miR-99a downregulation. J Cell Physiol 235(5):4399–4406. https://doi.org/10.1002/jcp.29316

    Article  CAS  PubMed  Google Scholar 

  158. Hong Y, Qin H, Li Y, Zhang Y, Zhuang X, Liu L, Lu K, Li L, Deng X, Liu F, Shi S, Liu G (2019) FNDC3B circular RNA promotes the migration and invasion of gastric cancer cells via the regulation of E-cadherin and CD44 expression. J Cell Physiol 234(11):19895–19910. https://doi.org/10.1002/jcp.28588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Wu G, Zhou W, Pan X, Sun Z, Sun Y, Xu H, Shi P, Li J, Gao L, Tian X (2020) Circular RNA profiling reveals exosomal circ_0006156 as a novel biomarker in papillary thyroid cancer. Mol Ther Nucleic Acids 19:1134–1144. https://doi.org/10.1016/j.omtn.2019.12.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. He YX, Ju H, Li N, Jiang YF, Zhao WJ, Song TT, Ren WH (2020) Association between hsa_circ_0006156 expression and incidence of gastric cancer. Eur Rev Med Pharmacol Sci 24(6):3030–3036. https://doi.org/10.26355/eurrev_202003_20667

    Article  PubMed  Google Scholar 

  161. Liu T, Song Z, Gai Y (2018) Circular RNA circ_0001649 acts as a prognostic biomarker and inhibits NSCLC progression via sponging miR-331-3p and miR-338-5p. Biochem Biophys Res Commun 503(3):1503–1509. https://doi.org/10.1016/j.bbrc.2018.07.070

    Article  CAS  PubMed  Google Scholar 

  162. Xing L, Zhang L, Feng Y, Cui Z, Ding L (2018) Downregulation of circular RNA hsa_circ_0001649 indicates poor prognosis for retinoblastoma and regulates cell proliferation and apoptosis via AKT/mTOR signaling pathway. Biomed Pharmacother 105:326–333. https://doi.org/10.1016/j.biopha.2018.05.141

    Article  CAS  PubMed  Google Scholar 

  163. Su Y, Xu C, Liu Y, Hu Y, Wu H (2019) Circular RNA hsa_circ_0001649 inhibits hepatocellular carcinoma progression via multiple miRNAs sponge. Aging 11(10):3362–3375. https://doi.org/10.18632/aging.101988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Qin M, Liu G, Huo X, Tao X, Sun X, Ge Z, Yang J, Fan J, Liu L, Qin W (2016) Hsa_circ_0001649: A circular RNA and potential novel biomarker for hepatocellular carcinoma. Cancer Biomarkers 16(1):161–169. https://doi.org/10.3233/cbm-150552

    Article  CAS  PubMed  Google Scholar 

  165. Xu Y, Yao Y, Zhong X, Leng K, Qin W, Qu L, Cui Y, Jiang X (2018) Downregulated circular RNA hsa_circ_0001649 regulates proliferation, migration and invasion in cholangiocarcinoma cells. Biochem Biophys Res Commun 496(2):455–461. https://doi.org/10.1016/j.bbrc.2018.01.077

    Article  CAS  PubMed  Google Scholar 

  166. Hao L, Rong W, Bai L, Cui H, Zhang S, Li Y, Chen D, Meng X (2019) Upregulated circular RNA circ_0007534 indicates an unfavorable prognosis in pancreatic ductal adenocarcinoma and regulates cell proliferation, apoptosis, and invasion by sponging miR-625 and miR-892b. J Cell Biochem 120(3):3780–3789. https://doi.org/10.1002/jcb.27658

    Article  CAS  PubMed  Google Scholar 

  167. Li GF, Li L, Yao ZQ, Zhuang SJ (2018) Hsa_circ_0007534/miR-761/ZIC5 regulatory loop modulates the proliferation and migration of glioma cells. Biochem Biophys Res Commun 499(4):765–771. https://doi.org/10.1016/j.bbrc.2018.03.219

    Article  CAS  PubMed  Google Scholar 

  168. Li B, Li X (2018) Overexpression of hsa_circ_0007534 predicts unfavorable prognosis for osteosarcoma and regulates cell growth and apoptosis by affecting AKT/GSK-3beta signaling pathway. Biomed Pharmacother 107:860–866. https://doi.org/10.1016/j.biopha.2018.08.086

    Article  CAS  PubMed  Google Scholar 

  169. Ding DY, Wang D, Shu ZB (2020) Hsa_circ_0007534 knockdown represses the development of colorectal cancer cells through regulating miR-613/SLC25A22 axis. Eur Rev Med Pharmacol Sci 24(6):3004–3022. https://doi.org/10.26355/eurrev_202003_20665

    Article  PubMed  Google Scholar 

  170. Westholm JO, Miura P, Olson S, Shenker S, Joseph B, Sanfilippo P, Celniker SE, Graveley BR, Lai EC (2014) Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. Cell Rep 9(5):1966–1980. https://doi.org/10.1016/j.celrep.2014.10.062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Xiao MS, Wilusz JE (2019) An improved method for circular RNA purification using RNase R that efficiently removes linear RNAs containing G-quadruplexes or structured 3′ ends. Nucleic Acids Res 47(16):8755–8769. https://doi.org/10.1093/nar/gkz576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Szabo L, Salzman J (2016) Detecting circular RNAs: bioinformatic and experimental challenges. Nat Rev Genet 17(11):679–692. https://doi.org/10.1038/nrg.2016.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Panda AC, De S, Grammatikakis I, Munk R, Yang X, Piao Y, Dudekula DB, Abdelmohsen K, Gorospe M (2017) High-purity circular RNA isolation method (RPAD) reveals vast collection of intronic circRNAs. Nucleic Acids Res 45(12):e116. https://doi.org/10.1093/nar/gkx297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Pandey PR, Rout PK, Das A, Gorospe M, Panda AC (2019) RPAD (RNase R treatment, polyadenylation, and poly(A)+ RNA depletion) method to isolate highly pure circular RNA. Methods (San Diego, Calif) 155:41–48. https://doi.org/10.1016/j.ymeth.2018.10.022

    Article  CAS  Google Scholar 

  175. Gao Y, Wang J, Zhao F (2015) CIRI: an efficient and unbiased algorithm for de novo circular RNA identification. Genome Biol 16(1):4. https://doi.org/10.1186/s13059-014-0571-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Chuang TJ, Wu CS, Chen CY, Hung LY, Chiang TW, Yang MY (2016) NCLscan: accurate identification of non-co-linear transcripts (fusion, trans-splicing and circular RNA) with a good balance between sensitivity and precision. Nucleic Acids Res 44(3):e29. https://doi.org/10.1093/nar/gkv1013

    Article  CAS  PubMed  Google Scholar 

  177. Szabo L, Morey R, Palpant NJ, Wang PL, Afari N, Jiang C, Parast MM, Murry CE, Laurent LC, Salzman J (2015) Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development. Genome Biol 16(1):126. https://doi.org/10.1186/s13059-015-0690-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Song X, Zhang N, Han P, Moon BS, Lai RK, Wang K, Lu W (2016) Circular RNA profile in gliomas revealed by identification tool UROBORUS. Nucleic Acids Res 44(9):e87. https://doi.org/10.1093/nar/gkw075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Carrara M, Fuschi P, Ivan C, Martelli F (2018) Circular RNAs: methodological challenges and perspectives in cardiovascular diseases. J Cell Mol Med 22(11):5176–5187. https://doi.org/10.1111/jcmm.13789

    Article  PubMed  PubMed Central  Google Scholar 

  180. Gao Y, Zhang J, Zhao F (2018) Circular RNA identification based on multiple seed matching. Brief Bioinform 19(5):803–810. https://doi.org/10.1093/bib/bbx014

    Article  CAS  PubMed  Google Scholar 

  181. Zeng X, Lin W, Guo M, Zou Q (2017) A comprehensive overview and evaluation of circular RNA detection tools. PLoS Comput Biol 13(6):e1005420. https://doi.org/10.1371/journal.pcbi.1005420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Hansen TB, Veno MT, Damgaard CK, Kjems J (2016) Comparison of circular RNA prediction tools. Nucleic Acids Res 44(6):e58. https://doi.org/10.1093/nar/gkv1458

    Article  PubMed  Google Scholar 

  183. Gao Y, Zhao F (2018) Computational strategies for exploring circular RNAs. Trends Genet 34(5):389–400. https://doi.org/10.1016/j.tig.2017.12.016

    Article  CAS  PubMed  Google Scholar 

  184. Chen B, Wei W, Huang X, Xie X, Kong Y, Dai D, Yang L, Wang J, Tang H, Xie X (2018) circEPSTI1 as a prognostic marker and mediator of triple-negative breast cancer progression. Theranostics 8(14):4003–4015. https://doi.org/10.7150/thno.24106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Chen L, Zhang S, Wu J, Cui J, Zhong L, Zeng L, Ge S (2017) circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family. Oncogene 36(32):4551–4561. https://doi.org/10.1038/onc.2017.89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Dou C, Cao Z, Yang B, Ding N, Hou T, Luo F, Kang F, Li J, Yang X, Jiang H, Xiang J, Quan H, Xu J, Dong S (2016) Changing expression profiles of lncRNAs, mRNAs, circRNAs and miRNAs during osteoclastogenesis. Sci Rep 6:21499. https://doi.org/10.1038/srep21499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Cortes-Lopez M, Miura P (2016) Emerging functions of circular RNAs. Yale J Biol Med 89(4):527–537

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Lin J, Liao S, Li E, Liu Z, Zheng R, Wu X, Zeng W (2020) circCYFIP2 acts as a sponge of miR-1205 and affects the expression of its target gene E2F1 to regulate gastric cancer metastasis. Mol Ther Nucleic Acids 21:121–132. https://doi.org/10.1016/j.omtn.2020.05.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Li G, Xue M, Yang F, Jin Y, Fan Y, Li W (2019) CircRBMS3 promotes gastric cancer tumorigenesis by regulating miR-153-SNAI1 axis. J Cell Physiol 234(3):3020–3028. https://doi.org/10.1002/jcp.27122

    Article  CAS  PubMed  Google Scholar 

  190. Wei S, Zheng Y, Jiang Y, Li X, Geng J, Shen Y, Li Q, Wang X, Zhao C, Chen Y, Qian Z, Zhou J, Li W (2019) The circRNA circPTPRA suppresses epithelial-mesenchymal transitioning and metastasis of NSCLC cells by sponging miR-96-5p. EBioMedicine 44:182–193. https://doi.org/10.1016/j.ebiom.2019.05.032

    Article  PubMed  PubMed Central  Google Scholar 

  191. Li L, Wei H, Zhang H, Xu F, Che G (2020) Circ_100565 promotes proliferation, migration and invasion in non-small cell lung cancer through upregulating HMGA2 via sponging miR-506-3p. Cancer Cell Int 20:160. https://doi.org/10.1186/s12935-020-01241-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Liu YT, Han XH, Xing PY, Hu XS, Hao XZ, Wang Y, Li JL, Zhang ZS, Yang ZH, Shi YK (2019) Circular RNA profiling identified as a biomarker for predicting the efficacy of Gefitinib therapy for non-small cell lung cancer. J Thoracic Dis 11(5):1779–1787. https://doi.org/10.21037/jtd.2019.05.22

    Article  Google Scholar 

  193. Dai X, Liu J, Guo X, Cheng A, Deng X, Guo L, Wang Z (2020) Circular RNA circFGD4 suppresses gastric cancer progression via modulating miR-532-3p/APC/β-catenin signalling pathway. Clin Sci (London, England: 1979) 134(13):1821–1839. https://doi.org/10.1042/cs20191043

    Article  CAS  Google Scholar 

  194. Dudekula DB, Panda AC, Grammatikakis I, De S, Abdelmohsen K, Gorospe M (2016) CircInteractome: a web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA Biol 13(1):34–42. https://doi.org/10.1080/15476286.2015.1128065

    Article  PubMed  Google Scholar 

  195. Zhong S, Wang J, Zhang Q, Xu H, Feng J (2018) CircPrimer: a software for annotating circRNAs and determining the specificity of circRNA primers. BMC Bioinformatics 19(1):292. https://doi.org/10.1186/s12859-018-2304-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Chuang TJ, Chen YJ, Chen CY, Mai TL, Wang YD, Yeh CS, Yang MY, Hsiao YT, Chang TH, Kuo TC, Cho HH, Shen CN, Kuo HC, Lu MY, Chen YH, Hsieh SC, Chiang TW (2018) Integrative transcriptome sequencing reveals extensive alternative trans-splicing and cis-backsplicing in human cells. Nucleic Acids Res 46(7):3671–3691. https://doi.org/10.1093/nar/gky032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Huang R, Zhang Y, Han B, Bai Y, Zhou R, Gan G, Chao J, Hu G, Yao H (2017) Circular RNA HIPK2 regulates astrocyte activation via cooperation of autophagy and ER stress by targeting MIR124-2HG. Autophagy 13(10):1722–1741. https://doi.org/10.1080/15548627.2017.1356975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Panda AC, Abdelmohsen K, Gorospe M (2017) RT-qPCR Detection of Senescence-Associated Circular RNAs. Methods Mol Biol (Clifton, NJ) 1534:79–87. https://doi.org/10.1007/978-1-4939-6670-7_7

    Article  CAS  Google Scholar 

  199. Panda AC, Gorospe M (2018) Detection and Analysis of Circular RNAs by RT-PCR. Bio Protoc 8(6):e2775. https://doi.org/10.21769/BioProtoc.2775

    Article  PubMed  PubMed Central  Google Scholar 

  200. Bachmayr-Heyda A, Reiner AT, Auer K, Sukhbaatar N, Aust S, Bachleitner-Hofmann T, Mesteri I, Grunt TW, Zeillinger R, Pils D (2015) Correlation of circular RNA abundance with proliferation--exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues. Sci Rep 5:8057. https://doi.org/10.1038/srep08057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Ma HB, Yao YN, Yu JJ, Chen XX, Li HF (2018) Extensive profiling of circular RNAs and the potential regulatory role of circRNA-000284 in cell proliferation and invasion of cervical cancer via sponging miR-506. Am J Transl Res 10(2):592–604

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Rochow H, Franz A, Jung M, Weickmann S, Ralla B, Kilic E, Stephan C, Fendler A, Jung K (2020) Instability of circular RNAs in clinical tissue samples impairs their reliable expression analysis using RT-qPCR: from the myth of their advantage as biomarkers to reality. Theranostics 10(20):9268–9279. https://doi.org/10.7150/thno.46341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Zhong S, Zhou S, Yang S, Yu X, Xu H, Wang J, Zhang Q, Lv M, Feng J (2019) Identification of internal control genes for circular RNAs. Biotechnol Lett 41(10):1111–1119. https://doi.org/10.1007/s10529-019-02723-0

    Article  CAS  PubMed  Google Scholar 

  204. Panda AC, Grammatikakis I, Kim KM, De S, Martindale JL, Munk R, Yang X, Abdelmohsen K, Gorospe M (2017) Identification of senescence-associated circular RNAs (SAC-RNAs) reveals senescence suppressor CircPVT1. Nucleic Acids Res 45(7):4021–4035. https://doi.org/10.1093/nar/gkw1201

    Article  CAS  PubMed  Google Scholar 

  205. Wang PL, Bao Y, Yee MC, Barrett SP, Hogan GJ, Olsen MN, Dinneny JR, Brown PO, Salzman J (2014) Circular RNA is expressed across the eukaryotic tree of life. PLoS One 9(6):e90859. https://doi.org/10.1371/journal.pone.0090859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Roy CK, Olson S, Graveley BR, Zamore PD, Moore MJ (2015) Assessing long-distance RNA sequence connectivity via RNA-templated DNA-DNA ligation. eLife 4:e03700. https://doi.org/10.7554/eLife.03700

    Article  PubMed Central  Google Scholar 

  207. Cocquet J, Chong A, Zhang G, Veitia RA (2006) Reverse transcriptase template switching and false alternative transcripts. Genomics 88(1):127–131. https://doi.org/10.1016/j.ygeno.2005.12.013

    Article  CAS  PubMed  Google Scholar 

  208. Abe N, Matsumoto K, Nishihara M, Nakano Y, Shibata A, Maruyama H, Shuto S, Matsuda A, Yoshida M, Ito Y, Abe H (2015) Rolling circle translation of circular RNA in living human cells. Sci Rep 5:16435. https://doi.org/10.1038/srep16435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Quail MA, Kozarewa I, Smith F, Scally A, Stephens PJ, Durbin R, Swerdlow H, Turner DJ (2008) A large genome center’s improvements to the Illumina sequencing system. Nat Methods 5(12):1005–1010. https://doi.org/10.1038/nmeth.1270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ, Bright IJ, Lucero MY, Hiddessen AL, Legler TC, Kitano TK, Hodel MR, Petersen JF, Wyatt PW, Steenblock ER, Shah PH, Bousse LJ, Troup CB, Mellen JC, Wittmann DK, Erndt NG, Cauley TH, Koehler RT, So AP, Dube S, Rose KA, Montesclaros L, Wang S, Stumbo DP, Hodges SP, Romine S, Milanovich FP, White HE, Regan JF, Karlin-Neumann GA, Hindson CM, Saxonov S, Colston BW (2011) High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem 83(22):8604–8610. https://doi.org/10.1021/ac202028g

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Quan PL, Sauzade M, Brouzes E (2018) dPCR: A Technology Review. Sensors (Basel) 18(4):1271. https://doi.org/10.3390/s18041271

    Article  CAS  Google Scholar 

  212. Li T, Shao Y, Fu L, Xie Y, Zhu L, Sun W, Yu R, Xiao B, Guo J (2018) Plasma circular RNA profiling of patients with gastric cancer and their droplet digital RT-PCR detection. J Mol Med (Berl) 96(1):85–96. https://doi.org/10.1007/s00109-017-1600-y

    Article  CAS  Google Scholar 

  213. Trayhurn P (1996) Northern blotting. Proc Nutr Soc 55(1B):583–589. https://doi.org/10.1079/pns19960051

    Article  CAS  PubMed  Google Scholar 

  214. Schneider T, Schreiner S, Preußer C, Bindereif A, Rossbach O (2018) Northern blot analysis of circular RNAs. Methods Mol Biol 1724:119–133. https://doi.org/10.1007/978-1-4939-7562-4_10

    Article  CAS  PubMed  Google Scholar 

  215. Wang X, Shan G (2018) Nonradioactive Northern Blot of circRNAs. Methods Mol Biol 1724:135–141. https://doi.org/10.1007/978-1-4939-7562-4_11

    Article  CAS  PubMed  Google Scholar 

  216. Tabak HF, Van der Horst G, Smit J, Winter AJ, Mul Y, Groot Koerkamp MJ (1988) Discrimination between RNA circles, interlocked RNA circles and lariats using two-dimensional polyacrylamide gel electrophoresis. Nucleic Acids Res 16(14A):6597–6605. https://doi.org/10.1093/nar/16.14.6597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Zirkel A, Papantonis A (2018) Detecting circular RNAs by RNA fluorescence in situ hybridization. Methods Mol Biol 1724:69–75. https://doi.org/10.1007/978-1-4939-7562-4_6

    Article  CAS  PubMed  Google Scholar 

  218. Zhang J, Liu H, Hou L, Wang G, Zhang R, Huang Y, Chen X, Zhu J (2017) Circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression. Mol Cancer 16(1):151. https://doi.org/10.1186/s12943-017-0719-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Liu H, Liu Y, Bian Z, Zhang J, Zhang R, Chen X, Huang Y, Wang Y, Zhu J (2018) Circular RNA YAP1 inhibits the proliferation and invasion of gastric cancer cells by regulating the miR-367-5p/p27 (Kip1) axis. Mol Cancer 17(1):151. https://doi.org/10.1186/s12943-018-0902-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Zhang J, Hou L, Liang R, Chen X, Zhang R, Chen W, Zhu J (2019) CircDLST promotes the tumorigenesis and metastasis of gastric cancer by sponging miR-502-5p and activating the NRAS/MEK1/ERK1/2 signaling. Mol Cancer 18(1):80. https://doi.org/10.1186/s12943-019-1015-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Liu Z, Zhou Y, Liang G, Ling Y, Tan W, Tan L, Andrews R, Zhong W, Zhang X, Song E, Gong C (2019) Circular RNA hsa_circ_001783 regulates breast cancer progression via sponging miR-200c-3p. Cell Death Dis 10(2):55. https://doi.org/10.1038/s41419-018-1287-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Kocks C, Boltengagen A, Piwecka M, Rybak-Wolf A, Rajewsky N (2018) Single-Molecule Fluorescence In Situ Hybridization (FISH) of Circular RNA CDR1as. Methods Mol Biol 1724:77–96. https://doi.org/10.1007/978-1-4939-7562-4_7

    Article  CAS  PubMed  Google Scholar 

  223. Wang L, Long H, Zheng Q, Bo X, Xiao X, Li B (2019) Circular RNA circRHOT1 promotes hepatocellular carcinoma progression by initiation of NR2F6 expression. Mol Cancer 18(1):119. https://doi.org/10.1186/s12943-019-1046-7

    Article  PubMed  PubMed Central  Google Scholar 

  224. Florkowski CM (2008) Sensitivity, specificity, receiver-operating characteristic (ROC) curves and likelihood ratios: communicating the performance of diagnostic tests. Clin Biochem Rev 29 Suppl 1(Suppl 1):S83–S87

    PubMed  Google Scholar 

  225. Shiu SY, Gatsonis C (2008) The predictive receiver operating characteristic curve for the joint assessment of the positive and negative predictive values. Phil Trans A Math Phys Eng Sci 366(1874):2313–2333. https://doi.org/10.1098/rsta.2008.0043

    Article  Google Scholar 

  226. Goel MK, Khanna P, Kishore J (2010) Understanding survival analysis: Kaplan-Meier estimate. Int J Ayurveda Res 1(4):274–278. https://doi.org/10.4103/0974-7788.76794

    Article  PubMed  PubMed Central  Google Scholar 

  227. Bland JM, Altman DG (2004) The logrank test. BMJ 328(7447):1073. https://doi.org/10.1136/bmj.328.7447.1073

    Article  PubMed  PubMed Central  Google Scholar 

  228. Savas S, Liu G, Xu W (2013) Special considerations in prognostic research in cancer involving genetic polymorphisms. BMC Med 11:149. https://doi.org/10.1186/1741-7015-11-149

    Article  PubMed  PubMed Central  Google Scholar 

  229. Costa MC, Enguita FJ (2020) Towards a universal nomenclature standardization for circular RNAs. Non-coding RNA Investig 4

    Google Scholar 

  230. Jiang XM, Li ZL, Li JL, Xu Y, Leng KM, Cui YF, Sun DJ (2018) A novel prognostic biomarker for cholangiocarcinoma: circRNA Cdr1as. Eur Rev Med Pharmacol Sci 22(2):365–371. https://doi.org/10.26355/eurrev_201801_14182

    Article  PubMed  Google Scholar 

  231. Sang M, Meng L, Liu S, Ding P, Chang S, Ju Y, Liu F, Gu L, Lian Y, Geng C (2018) Circular RNA ciRS-7 maintains metastatic phenotypes as a ceRNA of miR-1299 to target MMPs. Mol Cancer Res 16(11):1665–1675. https://doi.org/10.1158/1541-7786.mcr-18-0284

    Article  CAS  PubMed  Google Scholar 

  232. Xu L, Zhang M, Zheng X, Yi P, Lan C, Xu M (2017) The circular RNA ciRS-7 (Cdr1as) acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma. J Cancer Res Clin Oncol 143(1):17–27. https://doi.org/10.1007/s00432-016-2256-7

    Article  CAS  PubMed  Google Scholar 

  233. Zhang J, Hu H, Zhao Y, Zhao Y (2018) CDR1as is overexpressed in laryngeal squamous cell carcinoma to promote the tumour’s progression via miR-7 signals. Cell proliferation 51(6):e12521. https://doi.org/10.1111/cpr.12521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Xu B, Yang T, Wang Z, Zhang Y, Liu S, Shen M (2018) CircRNA CDR1as/miR-7 signals promote tumor growth of osteosarcoma with a potential therapeutic and diagnostic value. Cancer Manag Res 10:4871–4880. https://doi.org/10.2147/cmar.s178213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Li J, Guo R, Liu Q, Sun J, Wang H (2020) Circular RNA Circ-ITCH inhibits the malignant behaviors of cervical cancer by microRNA-93-5p/FOXK2 axis. Reprod Sci 27(3):860–868. https://doi.org/10.1007/s43032-020-00140-7

    Article  CAS  PubMed  Google Scholar 

  236. Ren C, Liu J, Zheng B, Yan P, Sun Y, Yue B (2019) The circular RNA circ-ITCH acts as a tumour suppressor in osteosarcoma via regulating miR-22. Artif Cells Nanomed Biotechnol 47(1):3359–3367. https://doi.org/10.1080/21691401.2019.1649273

    Article  CAS  PubMed  Google Scholar 

  237. Zhang R, Xu J, Zhao J, Wang X (2018) Silencing of hsa_circ_0007534 suppresses proliferation and induces apoptosis in colorectal cancer cells. Eur Rev Med Pharmacol Sci 22(1):118–126. https://doi.org/10.26355/eurrev_201801_14108

    Article  CAS  PubMed  Google Scholar 

  238. Rong X, Gao W, Yang X, Guo J (2019) Downregulation of hsa_circ_0007534 restricts the proliferation and invasion of cervical cancer through regulating miR-498/BMI-1 signaling. Life Sci 235:116785. https://doi.org/10.1016/j.lfs.2019.116785

    Article  CAS  PubMed  Google Scholar 

  239. Song L, Xiao Y (2018) Downregulation of hsa_circ_0007534 suppresses breast cancer cell proliferation and invasion by targeting miR-593/MUC19 signal pathway. Biochem Biophys Res Commun 503(4):2603–2610. https://doi.org/10.1016/j.bbrc.2018.08.007

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, Spain

    Carla Solé, Gartze Mentxaka & Charles H. Lawrie

  2. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

    Charles H. Lawrie

  3. Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Charles H. Lawrie

Authors
  1. Carla Solé
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  2. Gartze Mentxaka
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  3. Charles H. Lawrie
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Corresponding author

Correspondence to Charles H. Lawrie .

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Editors and Affiliations

  1. Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain

    Alfons Navarro

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Solé, C., Mentxaka, G., Lawrie, C.H. (2021). The Use of circRNAs as Biomarkers of Cancer. In: Navarro, A. (eds) Long Non-Coding RNAs in Cancer. Methods in Molecular Biology, vol 2348. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1581-2_21

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  • DOI: https://doi.org/10.1007/978-1-0716-1581-2_21

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