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Androgen receptor modulates metastatic routes of VHL wild-type clear cell renal cell carcinoma in an oxygen-dependent manner

Oncogene volume 39, pages 6677–6691 (2020)Cite this article

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Abstract

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.

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Fig. 1: Clinical association of the AR expression with VEGF-A and VEGF-C expression in VHL-wt ccRCC under normoxia vs hypoxia.
Fig. 2: AR regulated VEGF-A and VEGF-C expression in the VHL-wt ccRCC cells via an oxygen-dependent manner.
Fig. 3: The miR185-5p was a potential candidate post-transcriptionally targeting VEGF-A and VEGF-C in ccRCC VHL-wt cells.
Fig. 4: AR modulated VEGF-A and VEGF-C by transcriptional regulation of the miR185-5p expression via oxygen-dependent manner in VHL-wt ccRCC cells.
Fig. 5: VHL interacts with and suppresses AR transactivation via interruption of AR nuclear translocation.
Fig. 6: AR promoted hematogenous yet suppressed lymphatic-metastasis of late-stage VHL-wt ccRCC in vivo.
Fig. 7: AR promoted angiogenesis yet suppressed lymphangiogenesis by regulation of VEGF-A and VEGE-C under hypoxic conditions in late-stage VHL-wt ccRCC.
Fig. 8: Schematic illustration of VHL and AR roles in regulating of HIF/VEGF-A or VEGF-C signaling under normaxia vs hypoxia condition.

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Acknowledgements

This work was supported by George Whipple Professorship Endowment, and Beijing Natural Science Foundation (No. 7194319), and National Nature Science Foundation (No. 81972389).

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  1. These authors contributed equally: Qingbo Huang, Yin Sun, Wei Zhai, Xin Ma

Authors and Affiliations

  1. Department of Urology, Chinese PLA General Hospital, 100853, Beijing, China

    Qingbo Huang, Xin Ma, Donglai Shen, Songliang Du & Xu Zhang

  2. 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

    Qingbo Huang, Yin Sun, Wei Zhai, Bosen You, Yuanjie Niu & Chawnshang Chang

  3. Department of Urology, Renji Hospital, Jiao Tong University, Shanghai, 200127, China

    Wei Zhai

  4. Sex Hormone Research Center, Department of Urology, China Medical University/Hospital, Taichung, 404, Taiwan

    Chi-Ping Huang & Chawnshang Chang

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Huang, Q., Sun, Y., Zhai, W. et al. Androgen receptor modulates metastatic routes of VHL wild-type clear cell renal cell carcinoma in an oxygen-dependent manner. Oncogene 39, 6677–6691 (2020). https://doi.org/10.1038/s41388-020-01455-0

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