Abstract
Emerging evidences have suggested the vital roles of circular RNA (circRNA) in the human cancers. However, the underlying biological functions and biogenesis of circRNA in the oral squamous cell carcinoma (OSCC) is still ambiguous. Here, we investigate the oncogenic roles and biogenesis of the novel identified circRNA, circUHRF1 (hsa_circ_0002185), in the OSCC tumorigenesis. Results showed that circUHRF1 was markedly upregulated in the OSCC cells and tissue, besides, the overexpression was closely correlated with the poor prognosis of OSCC patients. Functionally, circUHRF1 promoted the proliferation, migration, invasion, and epithelial mesenchymal transformation (EMT) in vitro and the tumor growth in vivo. Mechanically, circUHRF1 acted as the sponge of miR-526b-5p, thereby positively regulating c-Myc. Transcription factor c-Myc could accelerate the transcription of TGF-β1 and ESRP1. Moreover, splicing factor ESRP1 promoted the circularization and biogenesis of circUHRF1 by targeting the flanking introns, forming the circUHRF1/miR-526b-5p/c-Myc/TGF-β1/ESRP1 feedback loop. In conclusion, our research identified the oncogenic roles of circUHRF1 in the OSCC tumorigenesis and EMT via circUHRF1/miR-526b-5p/c-Myc/TGF-β1/ESRP1 feedback loop, shedding light on the pathogenic mechanism of circUHRF1 for OSCC and providing the potential therapeutic target.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Change history
18 December 2019
A Correction to this paper has been published: https://doi.org/10.1038/s41418-019-0477-4
References
Alves AM, Diel LF, Lamers ML. Macrophages and prognosis of oral squamous cell carcinoma: A systematic review. J Oral Pathol Med. 2018;47:460–7.
Safi AF, Grochau K, Drebber U, Schick V, Thiele O, Backhaus T, et al. A novel histopathological scoring system for patients with oral squamous cell carcinoma. Clinical Oral Investig. 2019. https://doi.org/10.1007/s00784-019-02804-4.
Zhou MY, Yang JM, Xiong XD. The emerging landscape of circular RNA in cardiovascular diseases. J Mol Cell Cardiol. 2018;122:134–9.
Wu J, Qi X, Liu L, Hu X, Liu J, Yang J, et al. Emerging epigenetic regulation of circular RNAs in human cancer. Mol Ther Nucleic Acids. 2019;16:589–96.
Wu J, Zhao W, Wang Z, Xiang X, Zhang S, Liu L. Long non-coding RNA SNHG20 promotes the tumorigenesis of oral squamous cell carcinoma via targeting miR-197/LIN28 axis. J Cell Mol Med. 2019;23:680–8.
Meng S, Zhou H, Feng Z, Xu Z, Tang Y, Li P, et al. CircRNA: functions and properties of a novel potential biomarker for cancer. Mol Cancer. 2017;16:94.
Zhao W, Ma X, Liu L, Chen Q, Liu Z, Zhang Z, et al. SNHG20: A vital lncRNA in multiple human cancers. J Cell Physiol. 2019;234:14519–25.
Chen L, Zhang S, Wu J, Cui J, Zhong L, Zeng L, et al. circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family. Oncogene. 2017;36:4551–61.
Qu S, Liu Z, Yang X, Zhou J, Yu H, Zhang R, et al. The emerging functions and roles of circular RNAs in cancer. Cancer Lett. 2018;414:301–9.
Zhong Y, Du Y, Yang X, Mo Y, Fan C, Xiong F, et al. Circular RNAs function as ceRNAs to regulate and control human cancer progression. Mol Cancer. 2018;17:79.
Huang C, Shan G. What happens at or after transcription: Insights into circRNA biogenesis and function. Transcription. 2015;6:61–64.
Wilusz JE. A 360 degrees view of circular RNAs: from biogenesis to functions. Wiley Interdiscip Rev RNA. 2018;9:e1478.
El Marabti E, Younis I. The cancer spliceome: reprograming of alternative splicing in cancer. Front Mol Biosci. 2018;5:80.
Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, et al. The RNA binding protein quaking regulates formation of circRNAs. Cell. 2015;160:1125–34.
Gottgens EL, Span PN, Zegers MM. Roles and regulation of epithelial splicing regulatory proteins 1 and 2 in epithelial-mesenchymal transition. Int Rev Cell Mol Biol. 2016;327:163–94.
Matos ML, Lapyckyj L, Rosso M, Besso MJ, Mencucci MV, Briggiler CI, et al. Identification of a novel human E-Cadherin splice variant and assessment of its effects upon EMT-related events. J Cell Physiol. 2017;232:1368–86.
Lekva T, Berg JP, Lyle R, Heck A, Ringstad G, Olstad OK, et al. Epithelial splicing regulator protein 1 and alternative splicing in somatotroph adenomas. Endocrinology. 2013;154:3331–43.
Warzecha CC, Jiang P, Amirikian K, Dittmar KA, Lu H, Shen S, et al. An ESRP-regulated splicing programme is abrogated during the epithelial-mesenchymal transition. EMBO J. 2010;29:3286–3300.
Ishii H, Saitoh M, Sakamoto K, Kondo T, Katoh R, Tanaka S, et al. Epithelial splicing regulatory proteins 1 (ESRP1) and 2 (ESRP2) suppress cancer cell motility via different mechanisms. J Biol Chem. 2014;289:27386–99.
Horiguchi K, Sakamoto K, Koinuma D, Semba K, Inoue A, Inoue S, et al. TGF-beta drives epithelial-mesenchymal transition through deltaEF1-mediated downregulation of ESRP. Oncogene. 2012;31:3190–201.
Harvey SE, Xu Y, Lin X, Gao XD, Qiu Y, Ahn J, et al. Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT. RNA. 2018;24:1326–38.
Jeong HM, Han J, Lee SH, Park HJ, Lee HJ, Choi JS, et al. ESRP1 is overexpressed in ovarian cancer and promotes switching from mesenchymal to epithelial phenotype in ovarian cancer cells. Oncogenesis. 2017;6:e389.
Bose R, Ain R. Regulation of transcription by circular RNAs. Adv Exp Med Biol. 2018;1087:81–94.
Pallavi N, Nalabolu GRK, Hiremath SKS. Bcl-2 and c-Myc expression in oral dysplasia and oral squamous cell carcinoma: An immunohistochemical study to assess tumor progression. J Oral Maxillofac Pathol. 2018;22:325–31.
Sambandam Y, Sundaram K, Liu A, Kirkwood KL, Ries WL, Reddy SV. CXCL13 activation of c-Myc induces RANK ligand expression in stromal/preosteoblast cells in the oral squamous cell carcinoma tumor-bone microenvironment. Oncogene. 2013;32:97–105.
Zeng K, He B, Yang BB, Xu T, Chen X, Xu M, et al. The pro-metastasis effect of circANKS1B in breast cancer. Mol Cancer. 2018;17:160.
Yu CY, Li TC, Wu YY, Yeh CH, Chiang W, Chuang CY, et al. The circular RNA circBIRC6 participates in the molecular circuitry controlling human pluripotency. Nat Commun. 2017;8:1149.
Cui Y, Li C, Zeng C, Li J, Zhu Z, Chen W, et al. Tongmai Yangxin pills anti-oxidative stress alleviates cisplatin-induced cardiotoxicity: network pharmacology analysis and experimental evidence. Biomedicine Pharmacother. 2018;108:1081–9.
Ebbesen KK, Kjems J, Hansen TB. Circular RNAs: identification, biogenesis and function. Biochim Biophys Acta. 2016;1859:163–8.
Su C, Gao X, Yang W, Zhao Y, Fu X, Cui X, et al. Phosphorylation of Tudor-SN, a novel substrate of JNK, is involved in the efficient recruitment of Tudor-SN into stress granules. Biochim Biophys Acta Mol Cell Res. 2017;1864:562–71.
Chen LL. The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol. 2016;17:205–11.
Wang YF, Li BW, Sun S, Li X, Su W, Wang ZH, et al. Circular RNA expression in oral squamous cell carcinoma. Front Oncol. 2018;8:398.
Liang HF, Zhang XZ, Liu BG, Jia GT, Li WL. Circular RNA circ-ABCB10 promotes breast cancer proliferation and progression through sponging miR-1271. Am J Cancer Res. 2017;7:1566–76.
Li S, Zhang S, Chen J. c-Myc induced upregulation of long non-coding RNA SNHG16 enhances progression and carcinogenesis in oral squamous cell carcinoma. Cancer Gene Ther. 2019. https://doi.org/10.1038/s41417-018-0072-8.
Yang C, Yuan W, Yang X, Li P, Wang J, Han J, et al. Circular RNA circ-ITCH inhibits bladder cancer progression by sponging miR-17/miR-224 and regulatingp21, PTEN expression. Mol Cancer. 2018;17:19.
Meng J, Chen S, Han JX, Qian B, Wang XR, Zhong WL, et al. Twist1 regulates vimentin through Cul2 Circular RNA to promote EMT in hepatocellular carcinoma. Cancer Res. 2018;78:4150–62.
Yang J, Liu K, Yang J, Jin B, Chen H, Zhan X, et al. PIM1 induces cellular senescence through phosphorylation of UHRF1 at Ser311. Oncogene. 2017;36:4828–42.
Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014;56:55–66.
Wang R, Zhang S, Chen X, Li N, Li J, Jia R, et al. EIF4A3-induced circular RNA MMP9 (circMMP9) acts as a sponge of miR-124 and promotes glioblastoma multiforme cell tumorigenesis. Mol Cancer. 2018;17:166.
Han J, Meng J, Wang X, Yin S, Zhang Q, Liu H, et al. YY1 complex promotes Quaking expression via super-enhancer binding during EMT of hepatocellular carcinoma. Cancer Res. 2019;79:1451–64.
Li Q, Wang Y, Wu S, Zhou Z, Ding X, Shi R, et al. CircACC1 regulates assembly and activation of AMPK complex under metabolic stress. Cell Metab. 2019;30:157–173.e157.
Acknowledgements
This work was supported by National Natural Science Foundation of China (Grant/Award Numbers: 81701019, 81870763), Tianjin Science and Technology Commission General Project (Grant/Award Numbers: 18JCYBJC92400), Tianjin Stomatology Hospital Doctor/Master Key Project (Grant/Award Numbers: 2019BSZD06).
Author contributions
WZ, YC, and LL perform the experiments and write the paper. XQ, JL, XH, SM, YW, ZZ, and HL act as the assists. JW, ZL, and ZW are responsible for the designing and funding collection. All authors read and approved the final paper.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Wei Zhao, Yameng Cui, Lina Liu and Xiaoqian Qi are both first authors
Edited by D. Aberdam
Supplementary information
Rights and permissions
About this article
Cite this article
Zhao, W., Cui, Y., Liu, L. et al. Splicing factor derived circular RNA circUHRF1 accelerates oral squamous cell carcinoma tumorigenesis via feedback loop. Cell Death Differ 27, 919–933 (2020). https://doi.org/10.1038/s41418-019-0423-5
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41418-019-0423-5
This article is cited by
-
Transcriptome-scale analysis of functional alternative back-splicing events in colorectal cancer
Journal of Translational Medicine (2025)
-
Diagnostic and therapeutic potential of exosomal circRNAs in cancer: decoding the circular code toward precision medicine
Cancer Cell International (2025)
-
Circ_0008043 promotes the metastasis of hepatocellular carcinoma by regulating the miR-661/PLEKHG4B axis
Scientific Reports (2025)
-
HNRNPA2B1 confers immune escape of non-small cell lung cancer through targeting lactate/ferroptosis
Cell Death & Disease (2025)
-
CSF3R-AS promotes hepatocellular carcinoma progression and sorafenib resistance through the CSF3R/JAK2/STAT3 positive feedback loop
Cell Death & Disease (2025)
