Molecules and Cells

  • 제46권1호
  • /
  • Pages.33-40
  • /
  • 2023
  • /
  • 1016-8478(pISSN)
  • /
  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
권호 표지
DOI QR코드

DOI QR Code

Circular RNAs in and out of Cells: Therapeutic Usages of Circular RNAs

  • Mingyu Ju (Graduate School of Medical Science and Engineering, Korea Advanced Institute for Science and Technology (KAIST)) ;
  • Dayeon Kim (Graduate School of Medical Science and Engineering, Korea Advanced Institute for Science and Technology (KAIST)) ;
  • Geurim Son (Graduate School of Medical Science and Engineering, Korea Advanced Institute for Science and Technology (KAIST)) ;
  • Jinju Han (Graduate School of Medical Science and Engineering, Korea Advanced Institute for Science and Technology (KAIST))
  • 투고 : 2022.11.05
  • 심사 : 2022.11.23
  • 발행 : 2023.01.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

RNAs are versatile molecules that are primarily involved in gene regulation and can thus be widely used to advance the fields of therapeutics and diagnostics. In particular, circular RNAs which are highly stable, have emerged as strong candidates for use on next-generation therapeutic platforms. Endogenous circular RNAs control gene regulatory networks by interacting with other biomolecules or through translation into polypeptides. Circular RNAs exhibit cell-type specific expression patterns, which can be altered in tissues and body fluids depending on pathophysiological conditions. Circular RNAs that are aberrantly expressed in diseases can function as biomarkers or therapeutic targets. Moreover, exogenous circular RNAs synthesized in vitro can be introduced into cells as therapeutic molecules to modulate gene expression networks in vivo. Depending on the purpose, synthetic circular RNA sequences can either be identical to endogenous circular RNA sequences or artificially designed. In this review, we introduce the life cycle and known functions of intracellular circular RNAs. The current stage of endogenous circular RNAs as biomarkers and therapeutic targets is also described. Finally, approaches and considerations that are important for applying the available knowledge on endogenous circular RNAs to design exogenous circular RNAs for therapeutic purposes are presented.

키워드

과제정보

This work was supported by the Bio and Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science and ICT (NRF-2022M3E5F1016556). D.K. was supported by the Fostering the Next Generation of Researchers Program of the NRF of Korea (NRF-2022R1A6A3A13073152).

참고문헌

  1. Abdelmohsen, K., Panda, A.C., Munk, R., Grammatikakis, I., Dudekula, D.B., De, S., Kim, J., Noh, J.H., Kim, K.M., Martindale, J.L., et al. (2017). Identification of HuR target circular RNAs uncovers suppression of PABPN1 translation by CircPABPN1. RNA Biol. 14, 361-369. https://doi.org/10.1080/15476286.2017.1279788
  2. Abe, N., Kodama, A., and Abe, H. (2018). Preparation of circular RNA in vitro. Methods Mol. Biol. 1724, 181-192. https://doi.org/10.1007/978-1-4939-7562-4_15
  3. Aktas, T., Avsar Ilik, I., Maticzka, D., Bhardwaj, V., Pessoa Rodrigues, C., Mittler, G., Manke, T., Backofen, R., and Akhtar, A. (2017). DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome. Nature 544, 115-119. https://doi.org/10.1038/nature21715
  4. Ashwal-Fluss, R., Meyer, M., Pamudurti, N.R., Ivanov, A., Bartok, O., Hanan, M., Evantal, N., Memczak, S., Rajewsky, N., and Kadener, S. (2014). circRNA biogenesis competes with pre-mRNA splicing. Mol. Cell 56, 55-66. https://doi.org/10.1016/j.molcel.2014.08.019
  5. Bachmayr-Heyda, A., Reiner, A.T., Auer, K., Sukhbaatar, N., Aust, S., Bachleitner-Hofmann, T., Mesteri, I., Grunt, T.W., Zeillinger, R., and 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.
  6. Bahn, J.H., Zhang, Q., Li, F., Chan, T.M., Lin, X., Kim, Y., Wong, D.T., and Xiao, X. (2015). The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin. Chem. 61, 221-230. https://doi.org/10.1373/clinchem.2014.230433
  7. Chen, L., Wang, C., Sun, H., Wang, J., Liang, Y., Wang, Y., and Wong, G. (2021). The bioinformatics toolbox for circRNA discovery and analysis. Brief. Bioinform. 22, 1706-1728. https://doi.org/10.1093/bib/bbaa001
  8. Chen, R., Wang, S.K., Belk, J.A., Amaya, L., Li, Z., Cardenas, A., Abe, B.T., Chen, C.K., Wender, P.A., and Chang, H.Y. (2022). Engineering circular RNA  for enhanced protein production. Nat. Biotechnol. 2022 Jul 18 [Epub]. https://doi.org/10.1038/s41587-022-01393-0
  9. Chen, Y.G., Chen, R., Ahmad, S., Verma, R., Kasturi, S.P., Amaya, L., Broughton, J.P., Kim, J., Cadena, C., Pulendran, B., et al. (2019). N6- methyladenosine modification controls circular RNA immunity. Mol. Cell 76, 96-109.e9. https://doi.org/10.1016/j.molcel.2019.07.016
  10. Cocquerelle, C., Daubersies, P., Majerus, M.A., Kerckaert, J.P., and Bailleul, B. (1992). Splicing with inverted order of exons occurs proximal to large introns. EMBO J. 11, 1095-1098. https://doi.org/10.1002/j.1460-2075.1992.tb05148.x
  11. Conn, S.J., Pillman, K.A., Toubia, J., Conn, V.M., Salmanidis, M., Phillips, C.A., Roslan, S., Schreiber, A.W., Gregory, P.A., and Goodall, G.J. (2015). The RNA binding protein quaking regulates formation of circRNAs. Cell 160, 1125-1134. https://doi.org/10.1016/j.cell.2015.02.014
  12. Conn, V.M., Hugouvieux, V., Nayak, A., Conos, S.A., Capovilla, G., Cildir, G., Jourdain, A., Tergaonkar, V., Schmid, M., Zubieta, C., et al. (2017). A circRNA from SEPALLATA3 regulates splicing of its cognate mRNA through R-loop formation. Nat. Plants 3, 17053.
  13. Darbeheshti, F., Zokaei, E., Mansoori, Y., Emadi Allahyari, S., Kamaliyan, Z., Kadkhoda, S., Tavakkoly Bazzaz, J., Rezaei, N., and Shakoori, A. (2021). Circular RNA hsa_circ_0044234 as distinct molecular signature of triple negative breast cancer: a potential regulator of GATA3. Cancer Cell Int. 21, 312.
  14. Dolinnaya, N.G., Sokolova, N.I., Ashirbekova, D.T., and Shabarova, Z.A. (1991). The use of BrCN for assembling modified DNA duplexes and DNA-RNA hybrids; comparison with water-soluble carbodiimide. Nucleic Acids Res. 19, 3067-3072. https://doi.org/10.1093/nar/19.11.3067
  15. Errichelli, L., Dini Modigliani, S., Laneve, P., Colantoni, A., Legnini, I., Capauto, D., Rosa, A., De Santis, R., Scarfo, R., Peruzzi, G., et al. (2017). FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons. Nat. Commun. 8, 14741.
  16. Fan, C., Lei, X., Tie, J., Zhang, Y., Wu, F., and Pan, Y. (2021). CircR2Disease v2.0: an updated web server for experimentally validated circRNA-disease associations and its application. Genomics Proteomics Bioinformatics 2021 Nov 29 [Epub]. https://doi.org/10.1016/j.gpb.2021.10.002
  17. Fischer, J.W., Busa, V.F., Shao, Y., and Leung, A.K.L. (2020). Structure-mediated RNA decay by UPF1 and G3BP1. Mol. Cell 78, 70-84.e6. https://doi.org/10.1016/j.molcel.2020.01.021
  18. Gebetsberger, J. and Polacek, N. (2013). Slicing tRNAs to boost functional ncRNA diversity. RNA Biol. 10, 1798-1806. https://doi.org/10.4161/rna.27177
  19. Guarnerio, J., Zhang, Y., Cheloni, G., Panella, R., Mae Katon, J., Simpson, M., Matsumoto, A., Papa, A., Loretelli, C., Petri, A., et al. (2019). Intragenic antagonistic roles of protein and circRNA in tumorigenesis. Cell Res. 29, 628-640. https://doi.org/10.1038/s41422-019-0192-1
  20. Hanineva, A., Park, K.S., Wang, J.J., DeAngelis, M.M., Farkas, M.H., and Zhang, S.X. (2022). Emerging roles of circular RNAs in retinal diseases. Neural Regen. Res. 17, 1875-1880. https://doi.org/10.4103/1673-5374.335691
  21. Hansen, T.B., Jensen, T.I., Clausen, B.H., Bramsen, J.B., Finsen, B., Damgaard, C.K., and Kjems, J. (2013). Natural RNA circles function as efficient microRNA sponges. Nature 495, 384-388. https://doi.org/10.1038/nature11993
  22. Hodgson, J. (2020). The pandemic pipeline. Nat. Biotechnol. 38, 523-532. https://doi.org/10.1038/d41587-020-00005-z
  23. Hu, G., Zhai, S., Yu, S., Huang, Z., and Gao, R. (2021). Circular RNA circRHOBTB3 is downregulated in hepatocellular carcinoma and suppresses cell proliferation by inhibiting miR-18a maturation. Infect. Agent. Cancer 16, 48.
  24. Huang, A., Zheng, H., Wu, Z., Chen, M., and Huang, Y. (2020). Circular RNA-protein interactions: functions, mechanisms, and identification. Theranostics 10, 3503-3517. https://doi.org/10.7150/thno.42174
  25. Hutchins, E., Reiman, R., Winarta, J., Beecroft, T., Richholt, R., De Both, M., Shahbander, K., Carlson, E., Janss, A., Siniard, A., et al. (2021). Extracellular circular RNA profiles in plasma and urine of healthy, male college athletes. Sci. Data 8, 276.
  26. Ivanov, A., Memczak, S., Wyler, E., Torti, F., Porath, H.T., Orejuela, M.R., Piechotta, M., Levanon, E.Y., Landthaler, M., Dieterich, C., et al. (2015). Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep. 10, 170-177. https://doi.org/10.1016/j.celrep.2014.12.019
  27. Jeck, W.R. and Sharpless, N.E. (2014). Detecting and characterizing circular RNAs. Nat. Biotechnol. 32, 453-461. https://doi.org/10.1038/nbt.2890
  28. Jeck, W.R., Sorrentino, J.A., Wang, K., Slevin, M.K., Burd, C.E., Liu, J., Marzluff, W.F., and Sharpless, N.E. (2013). Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 19, 141-157. https://doi.org/10.1261/rna.035667.112
  29. Jiang, Q., Liu, C., Li, C.P., Xu, S.S., Yao, M.D., Ge, H.M., Sun, Y.N., Li, X.M., Zhang, S.J., Shan, K., et al. (2020). Circular RNA-ZNF532 regulates diabetes-induced retinal pericyte degeneration and vascular dysfunction. J. Clin. Invest. 130, 3833-3847. https://doi.org/10.1172/JCI123353
  30. Jost, I., Shalamova, L.A., Gerresheim, G.K., Niepmann, M., Bindereif, A., and Rossbach, O. (2018). Functional sequestration of microRNA-122 from Hepatitis C Virus by circular RNA sponges. RNA Biol. 15, 1032-1039. https://doi.org/10.1080/15476286.2018.1435248
  31. Jung, M.K. and Shin, E.C. (2021). Phenotypes and functions of SARS-CoV-2-reactive T cells. Mol. Cells 44, 401-407. https://doi.org/10.14348/molcells.2021.0079
  32. Koh, W., Pan, W., Gawad, C., Fan, H.C., Kerchner, G.A., Wyss-Coray, T., Blumenfeld, Y.J., El-Sayed, Y.Y., and Quake, S.R. (2014). Noninvasive in vivo monitoring of tissue-specific global gene expression in humans. Proc. Natl. Acad. Sci. U. S. A. 111, 7361-7366. https://doi.org/10.1073/pnas.1405528111
  33. Kristensen, L.S., Okholm, T.L.H., Veno, M.T., and Kjems, J. (2018). Circular RNAs are abundantly expressed and upregulated during human epidermal stem cell differentiation. RNA Biol. 15, 280-291. https://doi.org/10.1080/15476286.2017.1409931
  34. Kumar, P., Anaya, J., Mudunuri, S.B., and Dutta, A. (2014). Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets. BMC Biol. 12, 78.
  35. Lai, H., Li, Y., Zhang, H., Hu, J., Liao, J., Su, Y., Li, Q., Chen, B., Li, C., Wang, Z., et al. (2022). exoRBase 2.0: an atlas of mRNA, lncRNA and circRNA in extracellular vesicles from human biofluids. Nucleic Acids Res. 50(D1), D118-D128. https://doi.org/10.1093/nar/gkab1085
  36. Lavenniah, A., Luu, T.D.A., Li, Y.P., Lim, T.B., Jiang, J., Ackers-Johnson, M., and Foo, R.S. (2020). Engineered circular RNA sponges act as miRNA inhibitors to attenuate pressure overload-induced cardiac hypertrophy. Mol. Ther. 28, 1506-1517. https://doi.org/10.1016/j.ymthe.2020.04.006
  37. Lee, E. and Oh, J.E. (2021). Humoral immunity against SARS-CoV-2 and the impact on COVID-19 pathogenesis. Mol. Cells 44, 392-400. https://doi.org/10.14348/molcells.2021.0075
  38. Lee, Y.C., Wang, W.Y., Lin, H.H., Huang, Y.R., Lin, Y.C., and Hsiao, K.Y. (2022). The functional roles and regulation of circular RNAs during cellular stresses. Noncoding RNA 8, 38.
  39. Legnini, I., Di Timoteo, G., Rossi, F., Morlando, M., Briganti, F., Sthandier, O., Fatica, A., Santini, T., Andronache, A., Wade, M., et al. (2017). Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol. Cell 66, 22-37.e9. https://doi.org/10.1016/j.molcel.2017.02.017
  40. Lei, M., Zheng, G., Ning, Q., Zheng, J., and Dong, D. (2020). Translation and functional roles of circular RNAs in human cancer. Mol. Cancer 19, 30.
  41. Lener, T., Gimona, M., Aigner, L., Borger, V., Buzas, E., Camussi, G., Chaput, N., Chatterjee, D., Court, F.A., Del Portillo, H.A., et al. (2015). Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J. Extracell. Vesicles 4, 30087.
  42. Li, J., Chen, R., Zheng, Y., Yuan, W., Yang, T., Zhu, X., Yan, Y., Jin, B., Xu, W., Zhang, Z., et al. (2022). Engineered circular RNA circmiR-29b attenuates muscle atrophy by sponging miR-29b. Adv. Ther. (Weinh.) 5, 2200029.
  43. Li, M.L., Wang, W., and Jin, Z.B. (2021). Circular RNAs in the central nervous system. Front. Mol. Biosci. 8, 629593.
  44. Li, Z., Huang, C., Bao, C., Chen, L., Lin, M., Wang, X., Zhong, G., Yu, B., Hu, W., Dai, L., et al. (2015). Exon-intron circular RNAs regulate transcription in the nucleus. Nat. Struct. Mol. Biol. 22, 256-264. https://doi.org/10.1038/nsmb.2959
  45. Liang, W.C., Wong, C.W., Liang, P.P., Shi, M., Cao, Y., Rao, S.T., Tsui, S.K., Waye, M.M., Zhang, Q., Fu, W.M., et al. (2019). Translation of the circular RNA circbeta-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol. 20, 84.
  46. Mao, S., Zhang, W., Yang, F., Guo, Y., Wang, H., Wu, Y., Wang, R., Maskey, N., Zheng, Z., Li, C., et al. (2021). Hsa_circ_0004296 inhibits metastasis of prostate cancer by interacting with EIF4A3 to prevent nuclear export of ETS1 mRNA. J. Exp. Clin. Cancer Res. 40, 336.
  47. Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L., Mackowiak, S.D., Gregersen, L.H., Munschauer, M., et al. (2013). Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333-338. https://doi.org/10.1038/nature11928
  48. Memczak, S., Papavasileiou, P., Peters, O., and Rajewsky, N. (2015). Identification and characterization of circular RNAs as a new class of putative biomarkers in human blood. PLoS One 10, e0141214.
  49. Morris, K.V. and Mattick, J.S. (2014). The rise of regulatory RNA. Nat. Rev. Genet. 15, 423-437. https://doi.org/10.1038/nrg3722
  50. Nelson, J., Sorensen, E.W., Mintri, S., Rabideau, A.E., Zheng, W., Besin, G., Khatwani, N., Su, S.V., Miracco, E.J., Issa, W.J., et al. (2020). Impact of mRNA chemistry and manufacturing process on innate immune activation. Sci. Adv. 6, eaaz6893.
  51. Oh, C., Koh, D., Jeon, H.B., and Kim, K.M. (2022). The role of extracellular vesicles in senescence. Mol. Cells 45, 603-609. https://doi.org/10.14348/molcells.2022.0056
  52. Orlandini von Niessen, A.G., Poleganov, M.A., Rechner, C., Plaschke, A., Kranz, L.M., Fesser, S., Diken, M., Lower, M., Vallazza, B., Beissert, T., et al. (2019). Improving mRNA-based therapeutic gene delivery by expression-augmenting 3' UTRs identified by cellular library screening. Mol. Ther. 27, 824-836. https://doi.org/10.1016/j.ymthe.2018.12.011
  53. Pardi, N., Hogan, M.J., Porter, F.W., and Weissman, D. (2018). mRNA vaccines - a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261-279. https://doi.org/10.1038/nrd.2017.243
  54. Park, J.W., Lagniton, P.N.P., Liu, Y., and Xu, R.H. (2021). mRNA vaccines for COVID-19: what, why and how. Int. J. Biol. Sci. 17, 1446-1460. https://doi.org/10.7150/ijbs.59233
  55. Park, O.H., Ha, H., Lee, Y., Boo, S.H., Kwon, D.H., Song, H.K., and Kim, Y.K. (2019). Endoribonucleolytic cleavage of m(6)A-containing RNAs by RNase P/MRP complex. Mol. Cell 74, 494-507.e8. https://doi.org/10.1016/j.molcel.2019.02.034
  56. Qu, L., Yi, Z., Shen, Y., Lin, L., Chen, F., Xu, Y., Wu, Z., Tang, H., Zhang, X., Tian, F., et al. (2022). Circular RNA vaccines against SARS-CoV-2 and emerging variants. Cell 185, 1728-1744.e16. https://doi.org/10.1016/j.cell.2022.03.044
  57. Roy, S., Kanda, M., Nomura, S., Zhu, Z., Toiyama, Y., Taketomi, A., Goldenring, J., Baba, H., Kodera, Y., and Goel, A. (2022). Diagnostic efficacy of circular RNAs as noninvasive, liquid biopsy biomarkers for early detection of gastric cancer. Mol. Cancer 21, 42.
  58. Sakshi, S., Jayasuriya, R., Ganesan, K., Xu, B., and Ramkumar, K.M. (2021). Role of circRNA-miRNA-mRNA interaction network in diabetes and its associated complications. Mol. Ther. Nucleic Acids 26, 1291-1302. https://doi.org/10.1016/j.omtn.2021.11.007
  59. Salzman, J., Gawad, C., Wang, P.L., Lacayo, N., and Brown, P.O. (2012). Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One 7, e30733.
  60. Santer, L., Bar, C., and Thum, T. (2019). Circular RNAs: a novel class of functional RNA molecules with a therapeutic perspective. Mol. Ther. 27, 1350-1363. https://doi.org/10.1016/j.ymthe.2019.07.001
  61. Schreiner, S., Didio, A., Hung, L.H., and Bindereif, A. (2020). Design and application of circular RNAs with protein-sponge function. Nucleic Acids Res. 48, 12326-12335. https://doi.org/10.1093/nar/gkaa1085
  62. Stephenson, M.L. and Zamecnik, P.C. (1978). Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc. Natl. Acad. Sci. U. S. A. 75, 285-288. https://doi.org/10.1073/pnas.75.1.285
  63. Sun, J., Li, B., Shu, C., Ma, Q., and Wang, J. (2020). Functions and clinical significance of circular RNAs in glioma. Mol. Cancer 19, 34.
  64. Tusup, M., Kundig, T., and Pascolo, S. (2018). An eIF4G-recruiting aptamer increases the functionality of in vitro transcribed mRNA. EPH - Int. J. Med. Health Sci. 4, 29-37. https://doi.org/10.53555/eijmhs.v4i2.36
  65. Wang, H., Xiao, Y., Wu, L., and Ma, D. (2018). Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-000911/miR-449a pathway in breast carcinogenesis. Int. J. Oncol. 52, 743-754. https://doi.org/10.3892/ijo.2018.4265
  66. Wang, Y., Liu, J., Ma, J., Sun, T., Zhou, Q., Wang, W., Wang, G., Wu, P., Wang, H., Jiang, L., et al. (2019). Exosomal circRNAs: biogenesis, effect and application in human diseases. Mol. Cancer 18, 116.
  67. Wang, Z., Yu, R., Chen, X., Bao, H., Cao, R., Li, A.N., Ou, Q., Tu, H.Y., Zhou, Q., Wu, X., et al. (2022). Clinical utility of cerebrospinal fluid-derived circular RNAs in lung adenocarcinoma patients with brain metastases. J. Transl. Med. 20, 74.
  68. Wesselhoeft, R.A., Kowalski, P.S., and Anderson, D.G. (2018). Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9, 2629.
  69. Xiao, M.S. and Wilusz, J.E. (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, 8755-8769. https://doi.org/10.1093/nar/gkz576
  70. Xu, X., Zhang, J., Tian, Y., Gao, Y., Dong, X., Chen, W., Yuan, X., Yin, W., Xu, J., Chen, K., et al. (2020). CircRNA inhibits DNA damage repair by interacting with host gene. Mol. Cancer 19, 128.
  71. Yang, Y., Gao, X., Zhang, M., Yan, S., Sun, C., Xiao, F., Huang, N., Yang, X., Zhao, K., Zhou, H., et al. (2018). Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis. J. Natl. Cancer Inst. 110, 304-315. https://doi.org/10.1093/jnci/djx166
  72. Zeng, Y., Du, W.W., Wu, Y., Yang, Z., Awan, F.M., Li, X., Yang, W., Zhang, C., Yang, Q., Yee, A., et al. (2017). A circular RNA binds to and activates AKT phosphorylation and nuclear localization reducing apoptosis and enhancing cardiac repair. Theranostics 7, 3842-3855. https://doi.org/10.7150/thno.19764
  73. Zhang, J., Zhang, X., Li, C., Yue, L., Ding, N., Riordan, T., Yang, L., Li, Y., Jen, C., Lin, S., et al. (2019). Circular RNA profiling provides insights into their subcellular distribution and molecular characteristics in HepG2 cells. RNA Biol. 16, 220-232. https://doi.org/10.1080/15476286.2019.1565284
  74. Zhang, M., Huang, N., Yang, X., Luo, J., Yan, S., Xiao, F., Chen, W., Gao, X., Zhao, K., Zhou, H., et al. (2018a). A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. Oncogene 37, 1805-1814. https://doi.org/10.1038/s41388-017-0019-9
  75. Zhang, M., Zhao, K., Xu, X., Yang, Y., Yan, S., Wei, P., Liu, H., Xu, J., Xiao, F., Zhou, H., et al. (2018b). A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat. Commun. 9, 4475.
  76. Zhang, Y., Nguyen, T.M., Zhang, X.O., Wang, L., Phan, T., Clohessy, J.G., and Pandolfi, P.P. (2021a). Optimized RNA-targeting CRISPR/Cas13d technology outperforms shRNA in identifying functional circRNAs. Genome Biol. 22, 41.
  77. Zhang, Y., Wang, Y., Su, X., Wang, P., and Lin, W. (2021b). The value of circulating circular RNA in cancer diagnosis, monitoring, prognosis, and guiding treatment. Front. Oncol. 11, 736546.
  78. Zhang, Y., Xue, W., Li, X., Zhang, J., Chen, S., Zhang, J.L., Yang, L., and Chen, L.L. (2016). The biogenesis of nascent circular RNAs. Cell Rep. 15, 611-624. https://doi.org/10.1016/j.celrep.2016.03.058
  79. Zhang, Y., Zhang, X.O., Chen, T., Xiang, J.F., Yin, Q.F., Xing, Y.H., Zhu, S., Yang, L., and Chen, L.L. (2013). Circular intronic long noncoding RNAs. Mol. Cell 51, 792-806. https://doi.org/10.1016/j.molcel.2013.08.017
  80. Zhang, Z., Yang, T., and Xiao, J. (2018c). Circular RNAs: promising biomarkers for human diseases. EBioMedicine 34, 267-274. https://doi.org/10.1016/j.ebiom.2018.07.036
  81. Zheng, X., Chen, L., Zhou, Y., Wang, Q., Zheng, Z., Xu, B., Wu, C., Zhou, Q., Hu, W., Wu, C., et al. (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, 47.