Skip to main content

Advertisement

SpringerLink
Log in

Orphan nuclear receptor COUP-TFII is an oncogenic gene in renal cell carcinoma

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) may be an oncogenic gene in renal cell carcinoma (RCC). However, the direct association between COUP-TFII expression and patient survival has not been investigated in patients with RCC, and the molecular oncogenesis of COUP-TFII in RCC remains unclear.

Methods

The mRNA expression levels of COUP-TFII in the tumors of 283 patients with RCC were determined by RT-qPCR. The remaining 266 patients were categorized into low- and high-expression groups according to the cut off value generated by receiver operating curve (ROC) analysis. The function of COUP-TFII in RCC cells was tested by knockdown experiments in vitro.

Results

In the present study, it was revealed that the mRNA expression levels of COUP-TFII were significantly higher in tumors compared with those in adjacent non-cancerous tissues, and that the overexpression of COUP-TFII was strongly associated with poor patient survival. It was further demonstrated that knockdown of COUP-TFII suppressed proliferation, and induced apoptosis and cell cycle arrest in RCC cells in vitro. This also resulted in the activation of the mitochondria-mediated apoptosis pathway, impaired migration and invasion of RCC cells through epithelial–mesenchymal transition in vitro, and suppressed tumor growth in vivo. In addition, it was revealed that the induction of cell migration and invasion by COUP-TFII was mediated, at least in part, by integrin subunit β1.

Conclusions

In summary, the present study indicated that COUP-TFII is an oncogenic gene in RCC, and a potential therapeutic target for the treatment of the disease.

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

References

  1. Qin J, Chen X, Xie X, Tsai MJ, Tsai SY. COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis. Proc Natl Acad Sci U S A. 2010;107(8):3687–92.

    Article  CAS  Google Scholar 

  2. Zhang C, Han Y, Huang H, Qu L, Shou C. High NR2F2 transcript level is associated with increased survival and its expression inhibits TGF-β-dependent epithelial–mesenchymal transition in breast cancer. Breast Cancer Res Treat. 2014;147(2):265–81.

    Article  CAS  Google Scholar 

  3. Qin J, Chen X, Yu-Lee LY, Tsai MJ, Tsai SY. Nuclear receptor COUP-TFII controls pancreatic islet tumor angiogenesis by regulating vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling. Cancer Res. 2010;70(21):8812–21.

    Article  CAS  Google Scholar 

  4. Métivier R, Gay FA, Hübner MR, Flouriot G, Salbert G, Gannon F, Kah O, Pakdel F. Formation of an hER alpha-COUP-TFI complex enhances hER alpha AF-1 through Ser118 phosphorylation by MAPK. EMBO J. 2002;21(13):3443–53.

    Article  Google Scholar 

  5. Le Dily F, Métivier R, Guéguen MM, Le Péron C, Flouriot G, Tas P, Pakdel F. COUP-TFI modulates estrogen signaling and influences proliferation, survival and migration of breast cancer cells. Breast Cancer Res Treat. 2008;110(1):69–83.

    Article  Google Scholar 

  6. Klinge CM, Silver BF, Driscoll MD, Sathya G, Bambara RA, Hilf R. Chicken ovalbumin upstream promoter-transcription factor interacts with estrogen receptor, binds to estrogen response elements and half-sites, and inhibits estrogen-induced gene expression. J Biol Chem. 1997;272(50):31465–74.

    Article  CAS  Google Scholar 

  7. Riggs KA, Wickramasinghe NS, Cochrum RK, Watts MB, Klinge CM. Decreased chicken ovalbumin upstream promoter transcription factor II expression in tamoxifen-resistant breast cancer cells. Cancer Res. 2006;66(20):10188–98.

    Article  CAS  Google Scholar 

  8. Fan M, Yan PS, Hartman-Frey C, Chen L, Paik H, Oyer SL, Salisbury JD, Cheng AS, Li L, Abbosh PH, Huang TH, Nephew KP. Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Cancer Res. 2006;66(24):11954–66.

    Article  CAS  Google Scholar 

  9. Al-Rayyan N, Litchfield LM, Ivanova MM, Radde BN, Cheng A, Elbedewy A, Klinge CM. 5-Aza-2-deoxycytidine and trichostatin A increase COUP-TFII expression in antiestrogen-resistant breast cancer cell lines. Cancer Lett. 2014;347(1):139–50.

    Article  CAS  Google Scholar 

  10. Muscat GE, Eriksson NA, Byth K, Loi S, Graham D, Jindal S, Davis MJ, Clyne C, Funder JW, Simpson ER, Ragan MA, Kuczek E, Fuller PJ, Tilley WD, Leedman PJ, Clarke CL. Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer. Mol Endocrinol. 2013;27(2):350–65.

    Article  CAS  Google Scholar 

  11. Zhang C, Han Y, Huang H, Qu L, Shou C. High NR2F2 transcript level is associated with increased survival and its expression inhibits TGF-β-dependent epithelial–mesenchymal transition in breast cancer. Breast Cancer Res Treat. 2014;147(2):265–81.

    Article  CAS  Google Scholar 

  12. Zheng J, Qin W, Jiao D, Ren J, Wei M, Shi S, Xi W, Wang H, Yang AG, Huan Y, Wen W. Knockdown of COUP-TFII inhibits cell proliferation and induces apoptosis through upregulating BRCA1 in renal cell carcinoma cells. Int J Cancer. 2016;139(7):1574–85.

    Article  CAS  Google Scholar 

  13. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8.

    Article  CAS  Google Scholar 

  14. Yang YX, Wei L, Zhang YJ, Hayano T, Piñeiro Pereda MDP, Nakaoka H, Li Q, Barragán Mallofret I, Lu YZ, Tamagnone L, Inoue I, Li X, Luo JY, Zheng K, You H. Long non-coding RNA p10247, high expressed in breast cancer (lncRNA-BCHE), is correlated with metastasis. Clin Exp Metastasis. 2018;35(3):109–21.

    Article  CAS  Google Scholar 

  15. Bao Y, Gu D, Feng W, Sun X, Wang X, Zhang X, Shi Q, Cui G, Yu H, Tang C, Deng A. COUP-TFII regulates metastasis of colorectal adenocarcinoma cells by modulating Snail1. Br J Cancer. 2014;111(5):933–43.

    Article  CAS  Google Scholar 

  16. Gurevich F, Perazella MA. Renal effects of anti-angiogenesis therapy: update for the internist. Am J Med. 2009;122(4):322–8.

    Article  CAS  Google Scholar 

  17. Polvani S, Tarocchi M, Tempesti S, Mello T, Ceni E, Buccoliero F, D’Amico M, Boddi V, Farsi M, Nesi S, Nesi G, Milani S, Galli A. COUP-TFII in pancreatic adenocarcinoma: clinical implication for patient survival and tumorprogression. Int J Cancer. 2014;134(7):1648–58.

    Article  CAS  Google Scholar 

  18. Qin J, Wu SP, Creighton CJ, Dai F, Xie X, Cheng CM, Frolov A, Ayala G, Lin X, Feng XH, Ittmann MM, Tsai SJ, Tsai MJ, Tsai SY. COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. Nature. 2013;493(7431):236–40.

    Article  CAS  Google Scholar 

  19. Lin SC, Kao CY, Lee HJ, Creighton CJ, Ittmann MM, Tsai SJ, Tsai SY, Tsai MJ. Dysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer. Nat Commun. 2016;7:11418.

    Article  CAS  Google Scholar 

  20. Ding W, Zhang Y, Cai H, Liu G, Ye Y, Xu G, Wang H, Xiong D, Zhang C, Huang Z, Luo Q. Overexpression of COUP–TFII suppresses proliferation and metastasis of human gastric cancer cells. Mol Med Rep. 2018;17(2):2393–401.

    CAS  PubMed  Google Scholar 

  21. Hawkins SM, Loomans HA, Wan YW, Ghosh-Choudhury T, Coffey D, Xiao W, Liu Z, Sangi-Haghpeykar H, Anderson ML. Expression and functional pathway analysis of nuclear receptor NR2F2 in ovarian cancer. J Clin Endocrinol Metab. 2013;98(7):E1152–62.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nephrology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China

    X. Fang, C.-X. Liu, X.-R. Zeng, X.-M. Huang, W.-L. Chen & Y. Wang

  2. Department of Emergency, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China

    F. Ai

Authors
  1. X. Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C.-X. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X.-R. Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X.-M. Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W.-L. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F. Ai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YW and FA conceived and designed this study. XF, CXL, XRZ, XMH and WLC performed the research, XF wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Y. Wang or F. Ai.

Ethics declarations

Conflict of interest

The authors have declared that no conflicts of interest exist.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The ethical committee of The Central Hospital of Wuhan granted permission to perform the study on human subjects.

Informed consent

All participants provided informed consent prior to their participation.

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

Fang, X., Liu, CX., Zeng, XR. et al. Orphan nuclear receptor COUP-TFII is an oncogenic gene in renal cell carcinoma. Clin Transl Oncol 22, 772–781 (2020). https://doi.org/10.1007/s12094-019-02190-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-019-02190-z

Keywords

Search

Navigation