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.

Estrogen receptor β promotes renal cell carcinoma progression via regulating LncRNA HOTAIR-miR-138/200c/204/217 associated CeRNA network

Abstract

Recent studies indicated that the estrogen receptor beta (ERβ) could affect the progression of prostate and bladder tumors, however, its roles in the renal cell carcinoma (RCC), remain to be elucidated. Here, we provide clinical evidence that ERβ expression is correlated in a negative manner with the overall survival/disease-free survival in RCC patients. Mechanism dissection revealed that targeting ERβ with ERβ-shRNA and stimulating the transactivation of ERβ with 17β-estradiol or environmental endocrine disrupting chemicals, all resulted in altering the lncRNA HOTAIR expression. The ERβ-modulated HOTAIR is able to function via antagonizing several microRNAs, including miR-138, miR-200c, miR-204, or miR-217 to impact various oncogenes, including ADAM9, CCND2, EZH2, VEGFA, VIM, ZEB1, and ZEB2, to promote RCC proliferation and invasion. Together, the identification of the ERβ-HOTAIR axis may provide us new biomarkers and/or therapeutic targets to better suppress RCC progression in the future.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol. 2010;7:245–57.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

    Article  PubMed  Google Scholar 

  3. Powles T, Staehler M, Ljungberg B, Bensalah K, Canfield SE, Dabestani S, et al. European Association of Urology Guidelines for clear cell renal cancers that are resistant to vascular endothelial growth factor receptor-targeted therapy. Eur Urol. 2016;70:705–6.

    Article  PubMed  Google Scholar 

  4. Powles T, Staehler M, Ljungberg B, Bensalah K, Canfield SE, Dabestani S, et al. Updated EAU Guidelines for clear cell renal cancer patients who fail VEGF targeted therapy. Eur Urol. 2016;69:4–6.

    Article  PubMed  Google Scholar 

  5. Perkel JM. Visiting “noncodarnia”. BioTechniques. 2013;54:301. 3-4

    PubMed  CAS  Google Scholar 

  6. Spizzo R, Almeida MI, Colombatti A, Calin GA. Long non-coding RNAs and cancer: a new frontier of translational research? Oncogene. 2012;31:4577–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Yan X, Hu Z, Feng Y, Hu X, Yuan J, Zhao SD, et al. Comprehensive genomic characterization of long non-coding RNAs across human cancers. Cancer Cell. 2015;28:529–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Yang G, Lu X, Yuan L. LncRNA: a link between RNA and cancer. Biochim Et Biophys Acta. 2014;1839:1097–109.

    Article  CAS  Google Scholar 

  9. Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 2011;10:38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Sorensen KP, Thomassen M, Tan Q, Bak M, Cold S, Burton M, et al. Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer. Breast Cancer Res Treat. 2013;142:529–36.

    Article  PubMed  CAS  Google Scholar 

  12. Liu XH, Sun M, Nie FQ, Ge YB, Zhang EB, Yin DD, et al. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer. 2014;13:92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T, et al. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 2011;71:6320–6.

    Article  PubMed  CAS  Google Scholar 

  14. Jing L, Yuan W, Ruofan D, Jinjin Y, Haifeng Q. HOTAIR enhanced aggressive biological behaviors and induced radio-resistance via inhibiting p21 in cervical cancer. Tumour Biol. 2015;36:3611–9.

    Article  PubMed  CAS  Google Scholar 

  15. Hajjari M, Salavaty A. HOTAIR: an oncogenic long non-coding RNA in different cancers. Cancer Biol Med. 2015;12:1–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  16. Sassen S, Miska EA, Caldas C. MicroRNA: implications for cancer. Virchows Arch. 2008;452:1–10.

    Article  PubMed  CAS  Google Scholar 

  17. Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov. 2013;12:847–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Yoon JH, Abdelmohsen K, Gorospe M. Functional interactions among microRNAs and long noncoding RNAs. Semin Cell Dev Biol. 2014;34:9–14.

    Article  PubMed  CAS  Google Scholar 

  19. Kartha RV, Subramanian S. Competing endogenous RNAs (ceRNAs): new entrants to the intricacies of gene regulation. Front Genet. 2014;5:8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Younes M, Honma N. Estrogen receptor beta. Arch Pathol Lab Med. 2011;135:63–6.

    PubMed  Google Scholar 

  21. Paruthiyil S, Parmar H, Kerekatte V, Cunha GR, Firestone GL, Leitman DC. Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res. 2004;64:423–8.

    Article  PubMed  CAS  Google Scholar 

  22. Fujimura T, Takahashi S, Urano T, Ogawa S, Ouchi Y, Kitamura T, et al. Differential expression of estrogen receptor beta (ERbeta) and its C-terminal truncated splice variant ERbetacx as prognostic predictors in human prostatic cancer. Biochem Biophys Res Commun. 2001;289:692–9.

    Article  PubMed  CAS  Google Scholar 

  23. Hsu I, Chuang KL, Slavin S, Da J, Lim WX, Pang ST, et al. Suppression of ERbeta signaling via ERbeta knockout or antagonist protects against bladder cancer development. Carcinogenesis. 2014;35:651–61.

    Article  PubMed  CAS  Google Scholar 

  24. Batistatou A, Kyzas PA, Goussia A, Arkoumani E, Voulgaris S, Polyzoidis K, et al. Estrogen receptor beta (ERbeta) protein expression correlates with BAG-1 and prognosis in brain glial tumours. J Neuro-Oncol. 2006;77:17–23.

    Article  CAS  Google Scholar 

  25. Yu CP, Ho JY, Huang YT, Cha TL, Sun GH, Yu DS, et al. Estrogen inhibits renal cell carcinoma cell progression through estrogen receptor-beta activation. PloS ONE. 2013;8:e56667.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Klotz LV, Eichhorn ME, Schwarz B, Seeliger H, Angele MK, Jauch KW, et al. Targeting the vasculature of visceral tumors: novel insights and treatment perspectives. Langenbeck’s Arch Surg. 2012;397:569–78.

    Article  CAS  Google Scholar 

  27. Rapisarda A, Melillo G. Role of the VEGF/VEGFR axis in cancer biology and therapy. Adv Cancer Res. 2012;114:237–67.

    Article  PubMed  CAS  Google Scholar 

  28. Liu L, Xu Z, Zhong L, Wang H, Jiang S, Long Q, et al. Enhancer of zeste homolog 2 (EZH2) promotes tumour cell migration and invasion via epigenetic repression of E-cadherin in renal cell carcinoma. BJU Int. 2016;117:351–62.

    Article  PubMed  CAS  Google Scholar 

  29. Xu ZQ, Zhang L, Gao BS, Wan YG, Zhang XH, Chen B, et al. EZH2 promotes tumor progression by increasing VEGF expression in clear cell renal cell carcinoma. Clinical & translational oncology: official publication of the Federation of Spanish. Oncol Soc Natl Cancer Inst Mex. 2015;17:41–9.

    CAS  Google Scholar 

  30. Finley DS, Pantuck AJ, Belldegrun AS. Tumor biology and prognostic factors in renal cell carcinoma. Oncologist. 2011;16(Suppl 2):4–13.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kontovinis LF, Papazisis KT, Touplikioti P, Andreadis C, Mouratidou D, Kortsaris AH. Sunitinib treatment for patients with clear-cell metastatic renal cell carcinoma: clinical outcomes and plasma angiogenesis markers. BMC Cancer. 2009;9:82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Lee HW, Choe M. Expression of EZH2 in renal cell carcinoma as a novel prognostic marker. Pathol Int. 2012;62:735–41.

    Article  PubMed  CAS  Google Scholar 

  33. Wagener N, Macher-Goeppinger S, Pritsch M, Husing J, Hoppe-Seyler K, Schirmacher P, et al. Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma. BMC Cancer. 2010;10:524.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Wang X, Chen X, Han W, Ruan A, Chen L, Wang R, et al. miR-200c targets CDK2 and suppresses tumorigenesis in renal cell carcinoma. Mol Cancer Res. 2015;13:1567–77.

    Article  PubMed  CAS  Google Scholar 

  35. Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res. 2008;36:D154–8.

    Article  PubMed  CAS  Google Scholar 

  36. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23:8253–61.

    Article  PubMed  CAS  Google Scholar 

  37. Hobisch A, Culig Z, Radmayr C, Bartsch G, Klocker H, Hittmair A. Distant metastases from prostatic carcinoma express androgen receptor protein. Cancer Res. 1995;55:3068–72.

    PubMed  CAS  Google Scholar 

  38. Niu Y, Altuwaijri S, Lai KP, Wu CT, Ricke WA, Messing EM, et al. Androgen receptor is a tumor suppressor and proliferator in prostate cancer. Proc Natl Acad Sci USA. 2008;105:12182–7.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Niu Y, Altuwaijri S, Yeh S, Lai KP, Yu S, Chuang KH, et al. Targeting the stromal androgen receptor in primary prostate tumors at earlier stages. Proc Natl Acad Sci USA. 2008;105:12188–93.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Qin J, Lee HJ, Wu SP, Lin SC, Lanz RB, Creighton CJ, et al. Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer. J Clin Investig. 2014;124:5013–26.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Zingg D, Debbache J, Schaefer SM, Tuncer E, Frommel SC, Cheng P, et al. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nat Commun. 2015;6:6051.

    Article  PubMed  CAS  Google Scholar 

  42. Hibino S, Saito Y, Muramatsu T, Otani A, Kasai Y, Kimura M, et al. Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells. Oncogenesis. 2014;3:e104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Jones J, Otu H, Spentzos D, Kolia S, Inan M, Beecken WD, et al. Gene signatures of progression and metastasis in renal cell cancer. Clinical cancer research: an official journal of the American Association for. Cancer Res. 2005;11:5730–9.

    CAS  Google Scholar 

  44. Gertz J, Reddy TE, Varley KE, Garabedian MJ, Myers RM. Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012;22:2153–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Hall JM, Korach KS. Endocrine disrupting chemicals promote the growth of ovarian cancer cells via the ER-CXCL12-CXCR4 signaling axis. Mol Carcinog. 2013;52:715–25.

    Article  PubMed  CAS  Google Scholar 

  46. Zheng J, Li H, Zhu H, Xiao X, Ma Y. Genistein inhibits estradiol- and environmental endocrine disruptor-induced growth effects on neuroblastoma cells. Oncol Lett. 2013;5:1583–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Chiyomaru T, Fukuhara S, Saini S, Majid S, Deng G, Shahryari V, et al. Long non-coding RNA HOTAIR is targeted and regulated by miR-141 in human cancer cells. J Biol Chem. 2014;289:12550–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Chiyomaru T, Yamamura S, Fukuhara S, Yoshino H, Kinoshita T, Majid S, et al. Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR. PloS ONE. 2013;8:e70372.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Verkasalo PK, Appleby PN, Allen NE, Davey G, Adlercreutz H, Key TJ. Soya intake and plasma concentrations of daidzein and genistein: validity of dietary assessment among eighty British women (Oxford arm of the European Prospective Investigation into Cancer and Nutrition). Br J Nutr. 2001;86:415–21.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was partially supported by URMC Urology Department Research fund and George Whipple Professorship Endowment.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jun Qi or Shuyuan Yeh.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ding, J., Yeh, CR., Sun, Y. et al. Estrogen receptor β promotes renal cell carcinoma progression via regulating LncRNA HOTAIR-miR-138/200c/204/217 associated CeRNA network. Oncogene 37, 5037–5053 (2018). https://doi.org/10.1038/s41388-018-0175-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-018-0175-6

This article is cited by

Search

Quick links