Abstract
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 pathologic 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 was 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.
Highlights
Renal cell carcinoma (RCC), which originates in the proximal tubules, is one of the most lethal urologic malignancies and frequently spreads to distant organs, including lung, bone, and brain [1]
Inactivation of the von Hippel–Lindau (VHL) gene as a result of mutation or methylation prevents the degradation of the hypoxia-inducible factor (HIF), and the accumulation of HIF in the nucleus alters the regulation of downstream target genes, including vascular endothelial growth factor (VEGF), which is implicated in angiogenesis [5]
Western blotting indicated that increased SOX18 protein expression was present in six of the eight Clear cell renal cell carcinoma (ccRCC) tissues when compared with matched normal tissues (Fig. 1B)
Summary
Renal cell carcinoma (RCC), which originates in the proximal tubules, is one of the most lethal urologic malignancies and frequently spreads to distant organs, including lung, bone, and brain [1]. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC and accounts for approximately 70% of the disease [2]. Inactivation of the VHL gene as a result of mutation or methylation prevents the degradation of the hypoxia-inducible factor (HIF), and the accumulation of HIF in the nucleus alters the regulation of downstream target genes, including vascular endothelial growth factor (VEGF), which is implicated in angiogenesis [5]. These causal events are the rationale for using angiogenesis inhibitors to treat advanced ccRCC.
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