Androgen receptor modulates metastatic routes of VHL wild-type clear cell renal cell carcinoma in an oxygen-dependent manner.
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 HIF2?-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.
Mesh Terms:
3' Untranslated Regions, Animals, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Renal Cell, Cell Hypoxia, Cell Line, Tumor, Gene Knockdown Techniques, Humans, Kidney Neoplasms, Male, Mice, MicroRNAs, Oxygen, RNA Interference, Receptors, Androgen, Transcription, Genetic, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor C, Von Hippel-Lindau Tumor Suppressor Protein, Xenograft Model Antitumor Assays
3' Untranslated Regions, Animals, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Renal Cell, Cell Hypoxia, Cell Line, Tumor, Gene Knockdown Techniques, Humans, Kidney Neoplasms, Male, Mice, MicroRNAs, Oxygen, RNA Interference, Receptors, Androgen, Transcription, Genetic, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor C, Von Hippel-Lindau Tumor Suppressor Protein, Xenograft Model Antitumor Assays
Oncogene
Date: Dec. 01, 2019
PubMed ID: 32943729
View in: Pubmed Google Scholar
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