Huang Qingbo, Sun Yin, Ma Xin, Gao Yu, Li Xintao, Niu Yuanjie, Zhang Xu, Chang Chawnshang
Department of Urology, Chinese PLA General Hospital, Beijing, 100853, China.
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Nat Commun. 2017 Oct 13;8(1):918. doi: 10.1038/s41467-017-00701-6.
Clear cell renal cell carcinoma (ccRCC) is a gender-biased tumor. Here we report that there is also a gender difference between pulmonary metastasis and lymph node metastasis showing that the androgen receptor (AR)-positive ccRCC may prefer to metastasize to lung rather than to lymph nodes. A higher AR expression increases ccRCC hematogenous metastasis yet decreases ccRCC lymphatic metastases. Mechanism dissection indicates that AR enhances miR-185-5p expression via binding to the androgen response elements located on the promoter of miR-185-5p, which suppresses VEGF-C expression via binding to its 3' UTR. In contrast, AR-enhanced miR-185-5p also promotes HIF2α/VEGF-A expression via binding to the promoter region of HIF2α. Together, these results provide a unique mechanism by which AR can either increase or decrease ccRCC metastasis at different sites and may help us to develop combined therapies using anti-AR and anti-VEGF-C compounds to better suppress ccRCC progression.The incidence of renal cell carcinoma is higher in males than in females due to the different androgen receptor signaling but the molecular mechanisms behind this gender bias are unclear. Here the authors show how androgen receptor expression influences the metastatic route through the regulation of miR-185 and VEGF isoforms.
透明细胞肾细胞癌（ccRCC）是一种具有性别差异的肿瘤。在此我们报告，肺转移和淋巴结转移之间也存在性别差异，表明雄激素受体（AR）阳性的ccRCC可能更倾向于转移至肺部而非淋巴结。较高的AR表达增加ccRCC的血行转移，但减少ccRCC的淋巴转移。机制剖析表明，AR通过与位于miR-185-5p启动子上的雄激素反应元件结合来增强miR-185-5p的表达，而miR-185-5p通过与其3'UTR结合来抑制VEGF-C的表达。相反，AR增强的miR-185-5p还通过与HIF2α的启动子区域结合来促进HIF2α/VEGF-A的表达。总之，这些结果提供了一种独特的机制，通过该机制AR可以在不同部位增加或减少ccRCC转移，并可能有助于我们开发使用抗AR和抗VEGF-C化合物的联合疗法，以更好地抑制ccRCC进展。由于雄激素受体信号传导不同，肾细胞癌的发病率男性高于女性，但这种性别差异背后的分子机制尚不清楚。在此，作者展示了雄激素受体表达如何通过调节miR-185和VEGF异构体来影响转移途径。
