Skip to main content

Advertisement

SpringerLink
Log in

MiR-99a-5p Constrains Epithelial–Mesenchymal Transition of Cervical Squamous Cell Carcinoma Via Targeting CDC25A/IL6

  • Original Paper
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

MiR-99a-5p participates in processes and pathogenesis of varying diseases. However, the molecular mechanism of miR-99a-5p in human cervical squamous cell carcinoma (CSCC) remains unclear. Here, we found that miR-99a-5p was lowly expressed in CSCC cells and negatively associated with overall survival. In addition, cellular experiments including CCK8, wound healing, Transwell and flow cytometry assays disclosed that transfection of miR-99a-5p mimic could suppress the cell activity, cell migratory, and invasive abilities, and promote cell apoptosis, thus inhibiting the tumor progression of CSCC cells. Luciferase reporter gene assay indicated that miR-99a-5p targeted 3’-UTR of CDC25A. Also, enforced CDC25A level rescued the impact of miR-99a-5p on CSCC progression. Silencing CDC25A could restrain the mRNA and protein levels of IL-6 in CSCC. CDC25A overexpression or IL-6 treatment could attenuate inhibiting impact of miR-99a-5p overexpression on epithelial–mesenchymal transition (EMT). These findings suggested that miR-99a-5p may play an anti-tumor role in tumor metastasis by targeting CDC25A/IL6 to hamper EMT process, which revealed a novel molecular mechanism in CSCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

The data used to support the findings of this study are included within the article. The data and materials in the current study are available from the corresponding author on reasonable request.

References

  1. Cancer Genome Atlas Research, et al. (2017). Integrated genomic and molecular characterization of cervical cancer. Nature, 543, 378–384. https://doi.org/10.1038/nature21386

    Article  CAS  Google Scholar 

  2. Sung, H., et al. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71, 209–249. https://doi.org/10.3322/caac.21660

    Article  Google Scholar 

  3. Waggoner, S. E. (2003). Cervical cancer. Lancet, 361, 2217–2225. https://doi.org/10.1016/S0140-6736(03)13778-6

    Article  PubMed  Google Scholar 

  4. Crosbie, E. J., Einstein, M. H., Franceschi, S., & Kitchener, H. C. (2013). Human papillomavirus and cervical cancer. Lancet, 382, 889–899. https://doi.org/10.1016/S0140-6736(13)60022-7

    Article  PubMed  Google Scholar 

  5. Marth, C., et al. (2017). Cervical cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 28, 72–83. https://doi.org/10.1093/annonc/mdx220

    Article  Google Scholar 

  6. Zhu, H., et al. (2016). Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Des Devel Ther, 10, 1885–1895. https://doi.org/10.2147/DDDT.S106412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Croce, C. M. (2009). Causes and consequences of microRNA dysregulation in cancer. Nature Reviews Genetics, 10, 704–714. https://doi.org/10.1038/nrg2634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dillhoff, M., Liu, J., Frankel, W., Croce, C., & Bloomston, M. (2008). MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. Journal of Gastrointestinal Surgery, 12, 2171–2176. https://doi.org/10.1007/s11605-008-0584-x

    Article  PubMed  PubMed Central  Google Scholar 

  9. Li, J., et al. (2012). MicroRNA-223 functions as an oncogene in human gastric cancer by targeting FBXW7/hCdc4. Journal of Cancer Research and Clinical Oncology, 138, 763–774. https://doi.org/10.1007/s00432-012-1154-x

    Article  CAS  PubMed  Google Scholar 

  10. Zhu, L., Tu, H., Liang, Y., & Tang, D. (2018). MiR-218 produces anti-tumor effects on cervical cancer cells in vitro. World J Surg Oncol, 16, 204. https://doi.org/10.1186/s12957-018-1506-3

    Article  PubMed  PubMed Central  Google Scholar 

  11. Jiang, L., et al. (2018). MicroRNA-519d-3p Inhibits Proliferation and Promotes Apoptosis by Targeting HIF-2α in Cervical Cancer Under Hypoxic Conditions. Oncology research, 26, 1055–1062. https://doi.org/10.3727/096504018x15152056890500

    Article  PubMed  PubMed Central  Google Scholar 

  12. Li, P., et al. (2018). miR-182 promotes cell proliferation of cervical cancer cells by targeting adenomatous polyposis coli (APC) gene. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 34, 148–153.

    PubMed  Google Scholar 

  13. Galaktionov, K., & Beach, D. (1991). Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: Evidence for multiple roles of mitotic cyclins. Cell, 67, 1181–1194. https://doi.org/10.1016/0092-8674(91)90294-9

    Article  CAS  PubMed  Google Scholar 

  14. Lavecchia, A., Di Giovanni, C., & Novellino, E. (2010). Inhibitors of Cdc25 phosphatases as anticancer agents: A patent review. Expert Opinion on Therapeutic Patents, 20, 405–425. https://doi.org/10.1517/13543771003623232

    Article  CAS  PubMed  Google Scholar 

  15. Qin, H., & Liu, W. (2019). MicroRNA-99a-5p suppresses breast cancer progression and cell-cycle pathway through downregulating CDC25A. Journal of Cellular Physiology, 234, 3526–3537. https://doi.org/10.1002/jcp.26906

    Article  CAS  PubMed  Google Scholar 

  16. Al-Matouq, J., et al. (2017). Accumulation of cytoplasmic CDC25A in cutaneous squamous cell carcinoma leads to a dependency on CDC25A for cancer cell survival and tumor growth. Cancer Letters, 410, 41–49. https://doi.org/10.1016/j.canlet.2017.09.023

    Article  CAS  PubMed  Google Scholar 

  17. Bertoli, S., et al. (2015). CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia. Oncotarget, 6, 38061–38078. https://doi.org/10.18632/oncotarget.5706

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ataie-Kachoie, P., Pourgholami, M. H., Richardson, D. R., & Morris, D. L. (2014). Gene of the month: Interleukin 6 (IL-6). Journal of Clinical Pathology, 67, 932–937. https://doi.org/10.1136/jclinpath-2014-202493

    Article  CAS  PubMed  Google Scholar 

  19. Miao, J. W., Liu, L. J., & Huang, J. (2014). Interleukin-6-induced epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in human cervical carcinoma. International Journal of Oncology, 45, 165–176. https://doi.org/10.3892/ijo.2014.2422

    Article  CAS  PubMed  Google Scholar 

  20. Chen, S., et al. (2020). Silencing CDC25A inhibits the proliferation of liver cancer cells by downregulating IL6 in vitro and in vivo. International Journal of Molecular Medicine, 45, 743–752. https://doi.org/10.3892/ijmm.2020.4461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Robova, H., Rob, L., Halaska, M. J., Pluta, M., & Skapa, P. (2015). Review of neoadjuvant chemotherapy and trachelectomy: Which cervical cancer patients would be suitable for neoadjuvant chemotherapy followed by fertility-sparing surgery? Current Oncology Reports, 17, 446. https://doi.org/10.1007/s11912-015-0446-0

    Article  CAS  PubMed  Google Scholar 

  22. Kogo, R., et al. (2015). The microRNA-218~Survivin axis regulates migration, invasion, and lymph node metastasis in cervical cancer. Oncotarget, 6, 1090–1100. https://doi.org/10.18632/oncotarget.2836

    Article  PubMed  Google Scholar 

  23. Vandeperre, A., et al. (2015). Para-aortic lymph node metastases in locally advanced cervical cancer: Comparison between surgical staging and imaging. Gynecologic Oncology, 138, 299–303. https://doi.org/10.1016/j.ygyno.2015.05.021

    Article  PubMed  Google Scholar 

  24. Wong, H. A., et al. (2015). The cancer genome atlas analysis predicts MicroRNA for targeting cancer growth and vascularization in glioblastoma. Molecular Therapy, 23, 1234–1247. https://doi.org/10.1038/mt.2015.72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tsai, T. F., et al. (2018). miR-99a-5p acts as tumor suppressor via targeting to mTOR and enhances RAD001-induced apoptosis in human urinary bladder urothelial carcinoma cells. Oncotargets and Therapy, 11, 239–252. https://doi.org/10.2147/OTT.S114276

    Article  PubMed  PubMed Central  Google Scholar 

  26. Shi, Y., et al. (2017). MiR-99a-5p regulates proliferation, migration and invasion abilities of human oral carcinoma cells by targeting NOX4. Neoplasma, 64, 666–673. https://doi.org/10.4149/neo_2017_503

    Article  CAS  PubMed  Google Scholar 

  27. Chen, Y. T., et al. (2018). Biological role and clinical value of miR-99a-5p in head and neck squamous cell carcinoma (HNSCC): A bioinformatics-based study. FEBS Open Bio, 8, 1280–1298. https://doi.org/10.1002/2211-5463.12478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu, Y., Li, B., Yang, X., & Zhang, C. (2019). MiR-99a-5p inhibits bladder cancer cell proliferation by directly targeting mammalian target of rapamycin and predicts patient survival. Journal of Cellular Biochemistry, 120, 19330–19337. https://doi.org/10.1002/jcb.27318

    Article  CAS  PubMed  Google Scholar 

  29. Sun, X., & Yan, H. (2021). MicroRNA-99a-5p suppresses cell proliferation, migration, and invasion by targeting isoprenylcysteine carboxylmethyltransferase in oral squamous cell carcinoma. Journal of International Medical Research, 49, 300060520939031. https://doi.org/10.1177/0300060520939031

    Article  CAS  PubMed  Google Scholar 

  30. Kiyokawa, H., & Ray, D. (2008). In vivo roles of CDC25 phosphatases: Biological insight into the anti-cancer therapeutic targets. Anti-Cancer Agents in Medicinal Chemistry, 8, 832–836. https://doi.org/10.2174/187152008786847693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dozier, C., et al. (2017). CyclinD-CDK4/6 complexes phosphorylate CDC25A and regulate its stability. Oncogene, 36, 3781–3788. https://doi.org/10.1038/onc.2016.506

    Article  CAS  PubMed  Google Scholar 

  32. Liu, W., et al. (2018). SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A. Oncology Letters, 15, 5368–5374. https://doi.org/10.3892/ol.2018.7989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Biswas, S. C., Sanphui, P., Chatterjee, N., Kemeny, S., & Greene, L. A. (2017). Cdc25A phosphatase: A key cell cycle protein that regulates neuron death in disease and development. Cell Death & Disease, 8, e2692. https://doi.org/10.1038/cddis.2017.115

    Article  CAS  Google Scholar 

  34. Jiang, T., & Cheng, H. (2021). miR-34a-5p blocks cervical cancer growth and migration by downregulating CDC25A. Journal of B.U.ON., 26, 1768–1774.

    PubMed  Google Scholar 

  35. Fu, S., & Lin, J. (2018). Blocking Interleukin-6 and Interleukin-8 signaling inhibits cell viability, colony-forming activity, and cell migration in human triple-negative breast cancer and pancreatic cancer cells. Anticancer Research, 38, 6271–6279. https://doi.org/10.21873/anticanres.12983

    Article  CAS  PubMed  Google Scholar 

  36. Huang, Q., et al. (2018). 17beta-estradiol upregulates IL6 expression through the ERbeta pathway to promote lung adenocarcinoma progression. Journal of Experimental & Clinical Cancer Research, 37, 133. https://doi.org/10.1186/s13046-018-0804-5

    Article  CAS  Google Scholar 

  37. Wei, L. H., et al. (2001). Interleukin-6 in cervical cancer: The relationship with vascular endothelial growth factor. Gynecologic Oncology, 82, 49–56. https://doi.org/10.1006/gyno.2001.6235

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

No funding was received for this study.

Author information

Author notes

  1. Ailing Gu and Xudong Bao have contributed equally.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Wuxi No. 2 Chinese Medicine Hospital, 390 Xincheng Road, Binhu District, Wuxi City, 214026, Jiangsu Province, China

    Ailing Gu & Xudong Bao

Authors
  1. Ailing Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xudong Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Ailing Gu.

Ethics declarations

Conflict of interest

The authors declare that they have no potential conflicts of interest.

Ethical Approval

Not applicable.

Consent for Publication

All authors consent to submit the manuscript for publication.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gu, A., Bao, X. MiR-99a-5p Constrains Epithelial–Mesenchymal Transition of Cervical Squamous Cell Carcinoma Via Targeting CDC25A/IL6. Mol Biotechnol 64, 1234–1243 (2022). https://doi.org/10.1007/s12033-022-00496-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12033-022-00496-y

Keywords

Search

Navigation