The transcription factor SOX18, which was initially discovered as an activator of genetic transcription during embryogenesis, is now implicated in many diseases, including cancer, and is associated with the malignant tumor phenotype, angiogenesis, and lymphangiogenesis. However, the role of SOX18 in clear cell renal cell carcinoma (ccRCC) is not well understood. In the current study, SOX18 expression was evaluated in a 250-case cohort of primary ccRCC tissues that included 103 cases of matched normal kidney tissues and 21 cases of metastatic tissues. Functional and mechanistic analyses were performed in cells that had SOX18 either overexpressed or silenced to evaluate the effects of SOX18 on cell function, the cellular response to cabozantinib, and SOX18-mediated molecular mechanisms. Our data revealed that upregulation and nuclear translocation of SOX18 promoted ccRCC carcinogenesis and metastasis. Elevated SOX18 expression was associated with advanced pathological grades and TNM stages, as well as poor patient survival. SOX18 also regulated the cell cycle and the epithelial-mesenchymal transition to promote the malignant phenotype in ccRCC cells. The activation of EGF/EGFR and HGF/c-MET signaling in vitro and in vivo were induced by SOX18. Moreover, SOX18 activation bypassed the inhibitory effects of cabozantinib on cell proliferation, migration, and invasion. In conclusion, our data indicate that SOX18 may be a promising therapeutic target for ccRCC treatment.

Molecular cancer therapeutics. 2019 Sep 16 [Epub ahead of print]

Yin Huaqi, Qin Caipeng, Wang Qiang, Du Yiqing, Dai Xiang, Tang Xu, Zhang Xiaowei, Li Qing, Liu Shijun, Xu Tao

Urology, Peking University People’s Hospital., Urology, Peking University People’s Hospital .