Recent studies indicated that the androgen receptor (AR) plays important roles in modulating metastasis of VHL-mutant clear cell renal cell carcinoma (ccRCC). However, the precise mechanisms of AR roles in VHL wild-type (VHL-wt) ccRCC, remain unclear. Here we found that AR interacted with VHL to modulate the metastasis of VHL-wt ccRCC via an oxygen-dependent manner. Mechanism dissection revealed that AR could transcriptionally suppress the miR-185-5p expression in the presence of functional VHL-wt protein under a normoxic condition, which might then result in increasing the expression of VEGF-A and VEGF-C via targeting the 3'UTR of mRNAs at a post-transcriptional level. In contrast, under a hypoxic condition, AR could increase miR-185-5p expression to suppress VEGF-C expression, yet this miR-185-5p effect on VEGF-A was reversed via AR's positive regulation on the HIF2α-increased VEGF-A expression that resulted in increasing VEGF-A in the VHL-wt RCC cells. These distinct AR functions under different oxygen conditions may involve the VHL-impacted ubiquitination and nuclear localization of AR. The differential regulation of VEGF-A vs VEGF-C by AR may then result in differential impacts on the ccRCC metastatic destinations of VHL-wt ccRCC cells under different oxygen conditions. These finer mechanisms may help in the development of a novel therapy to better suppress the ccRCC progression under different oxygenization conditions.
Oncogene. 2020 Sep 17 [Epub ahead of print]
Qingbo Huang, Yin Sun, Wei Zhai, Xin Ma, Donglai Shen, Songliang Du, Bosen You, Yuanjie Niu, Chi-Ping Huang, Xu Zhang, Chawnshang Chang
Department of Urology, Chinese PLA General Hospital, 100853, Beijing, China., George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA., Sex Hormone Research Center, Department of Urology, China Medical University/Hospital, Taichung, 404, Taiwan., Department of Urology, Chinese PLA General Hospital, 100853, Beijing, China. ., George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA. .