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TR4 nuclear receptor promotes clear cell renal cell carcinoma (ccRCC) vasculogenic mimicry (VM) formation and metastasis via altering the miR490-3p/vimentin signals

Oncogene volume 37, pages 5901–5912 (2018)Cite this article

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Abstract

While TR4 nuclear receptor plays key roles to promote prostate cancer progression, its roles to alter the progression of clear cell renal cell carcinoma (ccRCC), remains unclear. Here, we demonstrate that TR4 can promote the ccRCC cell vasculogenic mimicry (VM) formation and its associated metastasis via modulating the miR490-3p/vimentin (VIM) signals. Mechanism dissection revealed that TR4 might increase the oncogene VIM expression via decreasing the miR-490-3p expression through direct binding to the TR4-response-elements (TR4REs) on the promoter region of miR-490-3p, which might then directly target the 3′ UTR of VIM-mRNA to increase its protein expression. Preclinical studies using the in vivo mouse model with xenografted RCC Caki-1 cells into the sub-renal capsule of nude mice also found that TR4 could promote the ccRCC VM and its associated metastasis via modulating the miR490-3p/VIM signals. Together, results from preclinical studies using multiple RCC cell lines and the in vivo mouse model all conclude that TR4 may play a key role to promote ccRCC VM formation and metastasis and targeting the newly identified TR4/miR-490-3p/VIM signals with small molecules may help us to develop a new therapeutic approach to better suppress the ccRCC metastasis.

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Acknowledgements

This work was supported by NIH grants (CA155477 and CA156700), George Whipple Professorship Endowment and Taiwan Department of Health Clinical Trial, Research Center of Excellence (DOH99-TD-B-111-004 to China Medical University, Taichung, Taiwan). We thank Karen Wolf for help preparing the manuscript.

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Authors and Affiliations

  1. Department of Urology, Guangdong Second Provincial General Hospital, Guangzhou, China

    Jian Bai, Xiaofu Qiu, Jun Zeng, Yangke Cai, Li Zuo & Guosheng Yang

  2. George Whipple Lab for Cancer Research, Departments of Urology and Pathology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA

    Jian Bai, Shuyuan Yeh, Xiaofu Qiu, Linyi Hu, Gonghui Li & Chawnshang Chang

  3. Department of Urology, Changzhou 2nd People’s Affiliated Hospital of Nanjing Medical University, Changzhou, China

    Li Zuo

  4. Sex Hormone Research Center, China Medical University and Hospital, Taichung, 404, Taiwan

    Chawnshang Chang

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Bai, J., Yeh, S., Qiu, X. et al. TR4 nuclear receptor promotes clear cell renal cell carcinoma (ccRCC) vasculogenic mimicry (VM) formation and metastasis via altering the miR490-3p/vimentin signals. Oncogene 37, 5901–5912 (2018). https://doi.org/10.1038/s41388-018-0269-1

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