Androgen receptor modulates metastatic routes of VHL wild-type clear cell renal cell carcinoma in an oxygen-dependent manner
Androgen receptor modulates metastatic routes of VHL wild-type clear cell renal cell carcinoma in an oxygen-dependent manner
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DOI：
10.1038/s41388-020-01455-0
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发表时间：
2020-09-17
期刊：
影响因子：
8
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
--
作者：
Huang, Qingbo;Sun, Yin;Chang, Chawnshang
近年来的研究表明雄激素受体（AR）在VHL突变型肾透明细胞癌（ccRCC）的转移中起重要作用。然而，AR在VHL野生型（VHL-wt）ccRCC中作用的精确机制仍不清楚。在这里，我们发现AR与VHL相互作用以通过氧依赖性方式调节VHL-wt ccRCC的转移。机制分析表明，AR在常氧条件下，在VHL-wt蛋白存在的情况下，可转录抑制miR-185- 5 p的表达，并可能通过在转录后水平靶向mRNA的3 ' UTR，从而增加VEGF-A和VEGF-C的表达。相反，在低氧条件下，AR可以增加miR-185- 5 p表达以抑制VEGF-C表达，然而这种miR-185- 5 p对VEGF-A的作用通过AR对HIF 2 α增加的VEGF-A表达的正调节而逆转，这导致VHL-wt RCC细胞中VEGF-A增加。这些不同的AR功能在不同的氧条件下可能涉及的VHL影响的泛素化和核定位的AR。AR对VEGF-A相对于VEGF-C的差异调节然后可导致在不同氧条件下对VHL-wt ccRCC细胞的ccRCC转移目的地的差异影响。这些更精细的机制可能有助于开发一种新的治疗方法，以更好地抑制不同氧合条件下的ccRCC进展。
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 alpha-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.