Androgen receptor (AR) suppresses miRNA-145 to promote renal cell carcinoma (RCC) progression independent of VHL status
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Yuan Chen1,3, Yin Sun3, Qun Rao2,3, Hua Xu3, Lei Li3 and Chawnshang Chang3,4
1 Sex Hormone Research Center, Department of Urology, Tongji Medical College/Hospital, Huazhong University of Science and Technology, Wuhan, China
2 Department of Gynaecology and Obstetrics, Tongji Medical College/Hospital, Huazhong University of Science and Technology, Wuhan, China
3 George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
4 Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan
Chawnshang Chang, email:
Hua Xu, email:
Keywords: renal cell carcinoma, androgen receptor, microRNA-145, HIF2α
Received: December 30, 2014 Accepted: April 23, 2015 Published: August 18, 2015
Mutational inactivation of the VHL tumor suppressor plays key roles in the development of renal cell carcinoma (RCC), and mutated VHL-mediated VEGF induction has become the main target for the current RCC therapy. Here we identified a signal pathway of VEGF induction by androgen receptor (AR)/miRNA-145 as a new target to suppress RCC progression. Mechanism dissection revealed that AR might function through binding to the androgen receptor element (ARE) located on the promoter region of miRNA-145 to suppress p53’s ability to induce expression of miRNA-145 that normally suppresses expression of HIF2α/VEGF/MMP9/CCND1. Suppressing AR with AR-shRNA or introducing exogenous miRNA-145 mimic can attenuate RCC progression independent of VHL status. MiR-145 mimic in preclinical RCC orthotopic xenograft mouse model revealed its efficacy in suppression of RCC progression. These results together identified signals by AR-suppressed miRNA-145 as a key player in the RCC progression via regulating HIF2α/VEGF/MMP9/CCND1 expression levels. Blockade of the newly identified signal by AR inhibition or miRNA-145 mimics has promising therapeutic benefit to suppress RCC progression.
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