Skip to main content
SpringerLink
Log in

Regulation of Cervical Cancer Development by a Novel Circ_0000212/miR-1236-3p/GREM1 ceRNA Crosstalk

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

Abstract

Circular RNAs (circRNAs) possess important functions in cervical carcinogenesis by operating as competing endogenous RNAs (ceRNAs). Our preliminary bioinformatics predicted the potential circ_0000212/microRNA (miR)-1236-3p/gremlin 1 (GREM1) ceRNA crosstalk. Thus, we further elucidated whether the novel ceRNA crosstalk can participate in cervical cancer development. Circ_0000212, miR-1236-3p and GREM1 were quantified by real-time quantitative polymerase chain reaction (qPCR) and immunoblotting. 5-ethynyl-2’-deoxyuridine (EdU) assay, flow cytometry, and tube formation assay were performed to assess cell proliferation, apoptosis and tube formation, respectively. Transwell assay was used to detect cell migration and invasion. Mouse xenografts were established to evaluate the role of circ_0000212 in vivo. Dual-luciferase reporter assay was performed to verify the direct relationship between miR-1236-3p and circ_0000212 or GREM1. Circ_0000212 expression was elevated in human cervical cancer. Silencing of endogenous circ_0000212 hindered cancer cell proliferation, motility and invasion and induced apoptosis, as well as diminished the tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. Circ_0000212 silencing also weakened tumor growth in vivo. Mechanistically, circ_0000212 directly bound to miR-1236-3p, and downregulation of miR-1236-3p reversed these effects of circ_0000212 silencing on cell malignant phenotypes and HUVEC tube formation. GREM1 was a direct miR-1236-3p target, and its expression was regulated by circ_0000212 through miR-1236-3p. Moreover, miR-1236-3p upregulation impeded cancer cell malignant phenotypes and HUVEC tube formation by targeting GREM1. Our findings identify a novel ceRNA regulatory network, circ_0000212/miR-1236-3p/GREM1 axis, in cervical carcinogenesis, and provide potential targets that can be explored for therapeutic interventions.

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
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., et al. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. A Cancer Journal for Clinicians, 71, 209–249.

    Article  Google Scholar 

  2. Musunuru, H. B., Pifer, P. M., Mohindra, P., Albuquerque, K., & Beriwal, S. (2021). Advances in management of locally advanced cervical cancer. Indian Journal of Medical Research, 154, 248–261.

    PubMed  PubMed Central  Google Scholar 

  3. Kunnummal, M., Angelin, M., & Das, A. V. (2021). PIWI proteins and piRNAs in cervical cancer: A propitious dart in cancer stem cell-targeted therapy. Human Cell, 34, 1629–1641.

    Article  CAS  PubMed  Google Scholar 

  4. Paskeh, M. D. A., Mirzaei, S., Gholami, M. H., Zarrabi, A., Zabolian, A., Hashemi, M., et al. (2021). Cervical cancer progression is regulated by SOX transcription factors: Revealing signaling networks and therapeutic strategies. Biomedicine & Pharmacotherapy, 144, 112335.

    Article  CAS  Google Scholar 

  5. Fang, J., Zhang, H., & Jin, S. (2014). Epigenetics and cervical cancer: From pathogenesis to therapy. Tumour Biology, 35, 5083–5093.

    Article  CAS  PubMed  Google Scholar 

  6. Chen, L., & Shan, G. (2021). CircRNA in cancer: Fundamental mechanism and clinical potential. Cancer Letters, 505, 49–57.

    Article  CAS  PubMed  Google Scholar 

  7. Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., et al. (2013). Circular RNAs are a large class of animal RNAs with regulatory potency. Nature, 495, 333–338.

    Article  CAS  PubMed  Google Scholar 

  8. Chaichian, S., Shafabakhsh, R., Mirhashemi, S. M., Moazzami, B., & Asemi, Z. (2020). Circular RNAs: A novel biomarker for cervical cancer. Journal of Cellular Physiology, 235, 718–724.

    Article  CAS  PubMed  Google Scholar 

  9. Wu, P., Li, C., Ye, D. M., Yu, K., Li, Y., Tang, H., et al. (2021). Circular RNA circEPSTI1 accelerates cervical cancer progression via miR-375/409-3P/515-5p-SLC7A11 axis. Aging (Albany NY), 13, 4663–4673.

    Article  CAS  PubMed  Google Scholar 

  10. Chen, Y., Geng, Y., Huang, J., Xi, D., Xu, G., Gu, W., et al. (2021). CircNEIL3 promotes cervical cancer cell proliferation by adsorbing miR-137 and upregulating KLF12. Cancer Cell International, 21, 34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liao, W., He, J., Disoma, C., Hu, Y., Li, J., Chen, G., et al. (2020). Hsa_circ_0107593 suppresses the progression of cervical cancer via sponging hsa-miR-20a-5p/93-5p/106b-5p. Frontiers in Oncology, 10, 590627.

    Article  PubMed  Google Scholar 

  12. Wang, Y., Miao, C., & Gao, X. (2021). TCEB3 is regulated by circ-0000212/miR-140-3p axis to promote the progression of cervical cancer. Oncotargets and Therapy, 14, 2853–2865.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wu, H., Tao, Y., Zhang, W., Wang, G., & Zhang, Q. (2021). circ-0000212 promotes cell proliferation of colorectal cancer by sponging miR-491 and modulating FOXP4 expression. Molecular Medicine Reports, 23, 300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bañuelos-Villegas, E. G., Pérez-yPérez, M. F., & Alvarez-Salas, L. M. (2021). Cervical cancer, papillomavirus, and miRNA dysfunction. Frontiers in Molecular Biosciences, 8, 758337.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Song, T. F., Xu, A. L., Chen, X. H., Gao, J. Y., Gao, F., & Kong, X. C. (2021). Circular RNA circRNA_101996 promoted cervical cancer development by regulating miR-1236-3p/TRIM37 axis. Kaohsiung Journal of Medical Sciences, 37, 547–561.

    Article  CAS  PubMed  Google Scholar 

  16. Kobayashi, H., Gieniec, K. A., Wright, J. A., Wang, T., Asai, N., Mizutani, Y., et al. (2021). The balance of stromal BMP signaling mediated by GREM1 and ISLR drives colorectal carcinogenesis. Gastroenterology, 160, 1224-1239.e1230.

    Article  CAS  PubMed  Google Scholar 

  17. Ren, J., Smid, M., Iaria, J., Salvatori, D. C. F., van Dam, H., Zhu, H. J., et al. (2019). Cancer-associated fibroblast-derived Gremlin 1 promotes breast cancer progression. Breast Cancer Research, 21, 109.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Namkoong, H., Shin, S. M., Kim, H. K., Ha, S. A., Cho, G. W., Hur, S. Y., et al. (2006). The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein. BMC Cancer, 6, 74.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Miao, H., Wang, N., Shi, L. X., Wang, Z., & Song, W. B. (2019). Overexpression of mircoRNA-137 inhibits cervical cancer cell invasion, migration and epithelial-mesenchymal transition by suppressing the TGF-β/smad pathway via binding to GREM1. Cancer Cell International, 19, 147.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sun, Q., Qi, X., Zhang, W., & Li, X. (2021). Knockdown of circRNA_0007534 suppresses the tumorigenesis of cervical cancer via miR-206/GREM1 axis. Cancer Cell International, 21, 54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dudekula, D. B., Panda, A. C., Grammatikakis, I., De, S., Abdelmohsen, K., & Gorospe, M. (2016). CircInteractome: A web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA Biology, 13, 34–42.

    Article  PubMed  Google Scholar 

  22. Lewis, B. P., Burge, C. B., & Bartel, D. P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 120, 15–20.

    Article  CAS  PubMed  Google Scholar 

  23. D’Souza, A., Pearman, C. M., Wang, Y., Nakao, S., Logantha, S., Cox, C., et al. (2017). Targeting miR-423-5p reverses exercise training-induced HCN4 channel remodeling and sinus bradycardia. Circulation Research, 121, 1058–1068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hatley, M. E., Patrick, D. M., Garcia, M. R., Richardson, J. A., Bassel-Duby, R., van Rooij, E., et al. (2010). Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell, 18, 282–293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen, S., Yang, X., Yu, C., Zhou, W., Xia, Q., Liu, Y., et al. (2021). The potential of circRNA as a novel diagnostic biomarker in cervical cancer. J Oncol, 2021, 5529486.

    PubMed  PubMed Central  Google Scholar 

  26. Yi, Y., Liu, Y., Wu, W., Wu, K., & Zhang, W. (2019). Reconstruction and analysis of circRNA-miRNA-mRNA network in the pathology of cervical cancer. Oncology Reports, 41, 2209–2225.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Guo, Y., Guo, Y., Chen, C., Fan, D., Wu, X., Zhao, L., et al. (2021). Circ3823 contributes to growth, metastasis and angiogenesis of colorectal cancer: Involvement of miR-30c-5p/TCF7 axis. Molecular Cancer, 20, 93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu, F., Zhang, X., Wu, F., & Peng, H. (2021). Hsa_circ_0088212-mediated miR-520 h/APOA1 axis inhibits osteosarcoma progression. Transl Oncol, 14, 101219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li, J., Chen, J., Hu, Z., & Xu, W. (2020). MicroRNA-1236-3p inhibits human osteosarcoma growth. Oncology Letters, 20, 367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao, Y., Zhou, H., Shen, J., Yang, S., Deng, K., Li, Q., et al. (2021). MiR-1236-3p inhibits the proliferation, invasion, and migration of colon cancer cells and hinders epithelial-mesenchymal transition by targeting DCLK3. Frontiers in Oncology, 11, 688882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yu, Z., Zhu, X., Li, Y., Liang, M., Liu, M., Liu, Z., et al. (2021). Circ-HMGA2 (hsa_circ_0027446) promotes the metastasis and epithelial-mesenchymal transition of lung adenocarcinoma cells through the miR-1236-3p/ZEB1 axis. Cell Death & Disease, 12, 313.

    Article  CAS  Google Scholar 

  32. Sato, M., Kawana, K., Fujimoto, A., Yoshida, M., Nakamura, H., Nishida, H., et al. (2016). Clinical significance of Gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance. Oncology Reports, 35, 391–397.

    Article  CAS  PubMed  Google Scholar 

  33. Miao, H., Song, W. B., Zhu, H., Wang, Q., & Tian, Y. (2020). Effect of GREM 1 gene on chemoradiotherapy sensitivity of cervical squamous carcinoma cells. European Review for Medical and Pharmacological Sciences, 24, 1072–1080.

    CAS  PubMed  Google Scholar 

  34. Yuan, Y., Cai, X., Shen, F., & Ma, F. (2021). HPV post-infection microenvironment and cervical cancer. Cancer Letters, 497, 243–254.

    Article  CAS  PubMed  Google Scholar 

  35. Casarotto, M., Fanetti, G., Guerrieri, R., Palazzari, E., Lupato, V., Steffan, A., et al. (2020). Beyond MicroRNAs: emerging role of other non-coding RNAs in HPV-driven cancers. Cancers (Basel), 12, 1246.

    Article  CAS  PubMed  Google Scholar 

  36. Tornesello, M. L., Faraonio, R., Buonaguro, L., Annunziata, C., Starita, N., Cerasuolo, A., et al. (2020). The role of microRNAs, long non-coding RNAs, and circular RNAs in cervical cancer. Frontiers in Oncology, 10, 150.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

None.

Author information

Author notes

  1. Yajun Zhang and Peili Liu have contributed equally to this study.

Authors and Affiliations

  1. Department of Pathology, Lianyungang Maternal and Child Health Hospital, Lianyungang, 222000, China

    Yajun Zhang & Li Yan

  2. Department of Gynaecology, Lianyungang Maternal and Child Health Hospital, No.669 Qindongmen Road, Haizhou, Lianyungang, 222000, China

    Peili Liu, Daoqing Wen, Haizhen Xiong & Zhe Zhou

Authors
  1. Yajun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peili Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daoqing Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haizhen Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhe Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peili Liu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 198 KB)

12033_2023_721_MOESM2_ESM.tif

Supplementary file2: Selection of miR-1236-3p. Real-time qPCR of miRNAs in C33A cells after transfection by si-circ_0000212 or si-NC. *P < 0.05 (TIF 230 KB)

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Liu, P., Wen, D. et al. Regulation of Cervical Cancer Development by a Novel Circ_0000212/miR-1236-3p/GREM1 ceRNA Crosstalk. Mol Biotechnol 65, 2086–2098 (2023). https://doi.org/10.1007/s12033-023-00721-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12033-023-00721-2

Keywords

Search

Navigation