Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

RETRACTED ARTICLE: microRNA-133a exerts tumor suppressive role in oral squamous cell carcinoma through the Notch signaling pathway via downregulation of CTBP2

This article was retracted on 31 July 2023

This article has been updated

Abstract

microRNAs (miRNAs) have been revealed to participate in some oral cancers and are proved to be effective. In the present study, we tried to explore the biological function of miR-133a in oral squamous cell carcinoma (OSCC) cells. The relationship that C-terminal-binding proteins 2 (CTBP2) was the putative target gene of miR-133a revealed from bioinformatics analysis was further was further validated by dual-luciferase reporter gene assay. In total, 40 patients with OSCC were enrolled for characterization of miR-133a, CTBP2, and Notch signaling pathway-related gene expression in clinical OSCC tissues. Low expression of miR-133a and high expression of CTBP2, Hes1, Notch-1, and Notch-3 were determined in OSCC tissues. OSCC cell lines were transfected with miR-133a inhibitor, miR-133a mimic, or shRNA targeting CTBP2, in response to which cell proliferation, migration, invasion, cell cycle, and apoptosis were evaluated. Transfection of miR-133a mimic induced apoptosis and inhibited OSCC cell proliferation, migration, and invasion and this was demonstrated to be attributable to decreased CTBP2 expression and suppression of the Notch signaling pathway. Taken together, we concluded that miR-133a acted as a tumor suppressor in OSCC through inhibition of the Notch signaling pathway via binding to CTBP2.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: CTBP2 and hsa-miR-133a are putative regulators in OSCC.
Fig. 2: CTBP2 was the target gene of miR-133a.
Fig. 3: Expression of CTBP2 and Notch signaling pathway-related factors were found high in OSCC tissues, while expression of miR-133a had opposite trend.
Fig. 4: MiR-133a can regulate the activation of notch pathway through CTBP2.
Fig. 5: Upregulated miR-133a inhibited the proliferation and the colony formation capacity of OSCC cells.
Fig. 6: Overexpression of miR-133a could effectively inhibit the invasion and migration of OSCC cells.
Fig. 7: Overexpression of miR-133a promoted cell cycle transition from G/G 1 to S phase.
Fig. 8: MiR-133a promoted apoptosis by negatively regulating of CTBP2.
Fig. 9: Model of molecular mechanisms involved in miR-133a regulation of OSCC cells.

Similar content being viewed by others

Change history

References

  1. Markopoulos AK. Current aspects on oral squamous cell carcinoma. Open Dent J 2012;6:126–30.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Thomson PJ. Perspectives on oral squamous cell carcinoma prevention-proliferation, position, progression and prediction. J Oral Pathol Med. 2018;47:803–7.

    Article  CAS  PubMed  Google Scholar 

  3. Gharat SA, Momin M, Bhavsar C. Oral squamous cell carcinoma: current treatment strategies and nanotechnology-based approaches for prevention and therapy. Crit Rev Ther Drug Carrier Syst. 2016;33:363–400.

    Article  PubMed  Google Scholar 

  4. Aali M, Mesgarzadeh AH, Najjary S, Abdolahi HM, Kojabad AB, Baradaran B. Evaluating the role of microRNAs alterations in oral squamous cell carcinoma. Gene. 2020;757:144936

    Article  CAS  PubMed  Google Scholar 

  5. Mazumder S, Datta S, Ray JG, Chaudhuri K, Chatterjee R. Liquid biopsy: miRNA as a potential biomarker in oral cancer. Cancer Epidemiol. 2019;58:137–45.

    Article  PubMed  Google Scholar 

  6. Gong Y, Ren J, Liu K, Tang LM. Tumor suppressor role of miR-133a in gastric cancer by repressing IGF1R. World J Gastroenterol. 2015;21:2949–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sui Y, Zhang X, Yang H, Wei W, Wang M. MicroRNA-133a acts as a tumour suppressor in breast cancer through targeting LASP1. Oncol Rep. 2018;39:473–82.

    CAS  PubMed  Google Scholar 

  8. Nohata N, Hanazawa T, Kikkawa N, Mutallip M, Fujimura L, Yoshino H, et al. Caveolin-1 mediates tumor cell migration and invasion and its regulation by miR-133a in head and neck squamous cell carcinoma. Int J Oncol. 2011;38:209–17.

    CAS  PubMed  Google Scholar 

  9. He B, Lin X, Tian F, Yu W, Qiao B. MiR-133a-3p inhibits oral squamous cell carcinoma (OSCC) proliferation and invasion by suppressing COL1A1. J Cell Biochem. 2018;119:338–46.

    Article  CAS  PubMed  Google Scholar 

  10. Wang Y, Che S, Cai G, He Y, Chen J, Xu W. Expression and prognostic significance of CTBP2 in human gliomas. Oncol Lett. 2016;12:2429–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dai F, Xuan Y, Jin JJ, Yu S, Long ZW, Cai H, et al. CtBP2 overexpression promotes tumor cell proliferation and invasion in gastric cancer and is associated with poor prognosis. Oncotarget. 2017;8:28736–49.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wang Y, Liu F, Mao F, Hang Q, Huang X, He S, et al. Interaction with cyclin H/cyclin-dependent kinase 7 (CCNH/CDK7) stabilizes C-terminal binding protein 2 (CtBP2) and promotes cancer cell migration. J Biol Chem. 2013;288:9028–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang G, Kang L, Chen J, Xue Y, Yang M, Qin B, et al. CtBP2 regulates TGFbeta2-induced epithelial-mesenchymal transition through notch signaling pathway in lens epithelial cells. Curr Eye Res. 2016;41:1057–63.

    Article  CAS  PubMed  Google Scholar 

  14. Torres A, Erices JI, Sanchez F, Ehrenfeld P, Turchi L, Virolle T, et al. Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia. Cancer Lett. 2019;446:112–22.

    Article  CAS  PubMed  Google Scholar 

  15. Aquino G, Pannone G, Santoro A, Liguori G, Franco R, Serpico R, et al. pEGFR-Tyr 845 expression as prognostic factors in oral squamous cell carcinoma: a tissue-microarray study with clinic-pathological correlations. Cancer Biol Ther. 2012;13:967–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yu XD, Yang JL, Zhang WL, Liu DX. Resveratrol inhibits oral squamous cell carcinoma through induction of apoptosis and G2/M phase cell cycle arrest. Tumour Biol. 2016;37:2871–7.

    Article  CAS  PubMed  Google Scholar 

  17. Gkouveris I, Nikitakis N, Karanikou M, Rassidakis G, Sklavounou A. Erk1/2 activation and modulation of STAT3 signaling in oral cancer. Oncol Rep. 2014;32:2175–82.

    Article  CAS  PubMed  Google Scholar 

  18. Salta E, Lau P, Sala Frigerio C, Coolen M, Bally-Cuif L, De, et al. A self-organizing miR-132/Ctbp2 circuit regulates bimodal notch signals and glial progenitor fate choice during spinal cord maturation. Dev Cell. 2014;30:423–36.

    Article  CAS  PubMed  Google Scholar 

  19. Yoshida R, Ito T, Hassan WA, Nakayama H. Notch1 in oral squamous cell carcinoma. Histol Histopathol. 2017;32:315–23.

    CAS  PubMed  Google Scholar 

  20. Weaver AN, Burch MB, Cooper TS, Della Manna DL, Wei S, Ojesina AI, et al. Notch signaling activation is associated with patient mortality and increased FGF1-mediated invasion in squamous cell carcinoma of the oral cavity. Mol Cancer Res. 2016;14:883–91.

    Article  CAS  PubMed  Google Scholar 

  21. El Arifeen S, Masanja H, Rahman AE. Child mortality: the challenge for India and the world. Lancet. 2017;390:1932–3.

    Article  PubMed  Google Scholar 

  22. Dumache R. Early diagnosis of oral squamous cell carcinoma by salivary microRNAs. Clin Lab. 2017;63:1771–6.

    Article  CAS  PubMed  Google Scholar 

  23. Schneider A, Victoria B, Lopez YN, Suchorska W, Barczak W, Sobecka A, et al. Tissue and serum microRNA profile of oral squamous cell carcinoma patients. Sci Rep. 2018;8:675.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Yan Y, Wang X, Veno MT, Bakholdt V, Sorensen JA, Krogdahl A, et al. Circulating miRNAs as biomarkers for oral squamous cell carcinoma recurrence in operated patients. Oncotarget. 2017;8:8206–14.

    Article  PubMed  Google Scholar 

  25. Ries J, Vairaktaris E, Kintopp R, Baran C, Neukam FW, Nkenke E. Alterations in miRNA expression patterns in whole blood of OSCC patients. Vivo. 2014;28:851–61.

    CAS  Google Scholar 

  26. Gao SH, Liu J, Zhang HJ, Zhao N, Zhang J. Low miR-133a expression is a predictor of outcome in patients with esophageal squamous cell cancer. Eur Rev Med Pharmacol Sci. 2016;20:3788–92.

    PubMed  Google Scholar 

  27. Xuan Q, Zhong X, Li W, Mo Z, Huang Y, Hu Y. CtBP2 is associated with angiogenesis and regulates the apoptosis of prostate cancer cells. Oncol Rep. 2017;38:1259–67.

    Article  CAS  PubMed  Google Scholar 

  28. Li Y, Chen D, Gao X, Li X, Shi G. LncRNA NEAT1 regulates cell viability and invasion in esophageal squamous cell carcinoma through the miR-129/CTBP2 Axis. Dis Markers. 2017;2017:5314649.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wei X, Yang Y, Jiang YJ, Lei JM, Guo JW, Xiao H. Relaxin ameliorates high glucose-induced cardiomyocyte hypertrophy and apoptosis via the Notch1 pathway. Exp Ther Med. 2018;15:691–8.

    CAS  PubMed  Google Scholar 

  30. Yoshida R, Nagata M, Nakayama H, Niimori-Kita K, Hassan W, Tanaka T, et al. The pathological significance of Notch1 in oral squamous cell carcinoma. Lab Invest. 2013;93:1068–81.

    Article  CAS  PubMed  Google Scholar 

  31. Dou XW, Liang YK, Lin HY, Wei XL, Zhang YQ, Bai JW, et al. Notch3 maintains luminal phenotype and suppresses tumorigenesis and metastasis of breast cancer via trans-activating estrogen receptor-alpha. Theranostics. 2017;7:4041–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li S, Qin X, Li Y, Zhang X, Niu R, Zhang H, et al. MiR-133a suppresses the migration and invasion of esophageal cancer cells by targeting the EMT regulator SOX4. Am J Transl Res. 2015;7:1390–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Guan C, Shi H, Wang H, Zhang J, Ni W, Chen B, et al. CtBP2 contributes to malignant development of human esophageal squamous cell carcinoma by regulation of p16INK4A. J Cell Biochem. 2013;114:1343–54.

    Article  CAS  PubMed  Google Scholar 

  34. Subramaniam D, Ponnurangam S, Ramamoorthy P, Standing D, Battafarano RJ, Anant S, et al. Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling. PLoS ONE. 2012;7:e30590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen G, Fang T, Huang Z, Qi Y, Du S, Di T, et al. MicroRNA-133a inhibits osteosarcoma cells proliferation and invasion via targeting IGF-1R. Cell Physiol Biochem. 2016;38:598–608.

    Article  CAS  PubMed  Google Scholar 

  36. Yan ZY, Luo ZQ, Zhang LJ, Li J, Liu JQ. Integrated analysis and microRNA expression profiling identified seven miRNAs associated with progression of oral squamous cell carcinoma. J Cell Physiol. 2017;232:2178–85.

    Article  CAS  PubMed  Google Scholar 

  37. Moriya Y, Nohata N, Kinoshita T, Mutallip M, Okamoto T, Yoshida S, et al. Tumor suppressive microRNA-133a regulates novel molecular networks in lung squamous cell carcinoma. J Hum Genet. 2012;57:38–45.

    Article  CAS  PubMed  Google Scholar 

  38. Kinoshita T, Nohata N, Watanabe-Takano H, Yoshino H, Hidaka H, Fujimura L, et al. Actin-related protein 2/3 complex subunit 5 (ARPC5) contributes to cell migration and invasion and is directly regulated by tumor-suppressive microRNA-133a in head and neck squamous cell carcinoma. Int J Oncol. 2012;40:1770–8.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Baoliang Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest

Ethics

The study was approved by the Institutional Review Board of Linyi People’s Hospital and in accordance with the declaration of Helsinki. Written informed consent was obtained from each participant.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article has been retracted. Please see the retraction notice for more detail:https://doi.org/10.1038/s41417-023-00649-4

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, W., Shi, X. & Wang, B. RETRACTED ARTICLE: microRNA-133a exerts tumor suppressive role in oral squamous cell carcinoma through the Notch signaling pathway via downregulation of CTBP2. Cancer Gene Ther 29, 62–72 (2022). https://doi.org/10.1038/s41417-020-00289-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-020-00289-y

This article is cited by

Search

Quick links