pVHL status in clear cell renal cell carcinoma regulates HIF-α and E-cadherin expression levels and their implications for tumor progression.

OBJECTIVES: This study aimed to determine the effects of von Hippel-Lindau protein (VHL) expression on hypoxia-inducible factor (HIF) and E-cadherin proteins. Furthermore, to evaluate the influence of the VHL-HIF-E-cadherin pathway in clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: This study used tissue samples collected from 150 patients with ccRCC and 24 adjacent kidney cortex samples. Immunoblotting was performed to measure the expression levels of VHL and E-cadherin. Additionally, nuclear expression of HIF-α was evaluated by immunohistochemistry (IHC) using a tissue microarray (TMA). RESULTS: pVHL levels were lower in ccRCC than in the adjacent kidney cortex; however, pVHL levels showed no correlation with clinicopathological parameters. Nuclear HIF-1α levels were higher in stage IV tumors, whereas HIF-2α levels increased with tumor size. No correlation was observed between HIF-3α levels and clinicopathological parameters. E-cadherin protein expression was reduced in ccRCC tissues and in higher-stage and larger tumors. In pVHL-high ccRCC, E-cadherin levels were lower in advanced-stage and larger tumors. Higher levels of HIF-1α and HIF-3α were observed in pVHL-low tumors. E-cadherin expression negatively correlated with nuclear HIF-1α expression. In pVHL-high ccRCCs, E-cadherin was negatively correlated with HIF-1α, while in pVHL-low ccRCCs, E-cadherin was negatively correlated with HIF-2α. E-cadherin was not associated with cancer-specific survival in patients with pVHL-low tumors, whereas E-cadherin expression was linked to improved survival in patients with pVHL-high tumors. CONCLUSION: VHL inactivation causes HIF-α activation and suppresses E-cadherin expression, thereby promoting ccRCC progression. This study provides insights into the potential biomarkers and therapeutic targets for ccRCC treatment.