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

## TL;DR

This study explores how the VHL protein affects HIF and E-cadherin in kidney cancer, linking these changes to tumor progression and patient outcomes.

## Contribution

The study reveals how pVHL status influences HIF-α and E-cadherin levels in clear cell renal cell carcinoma, offering new insights into tumor progression mechanisms.

## Key findings

- pVHL levels are lower in ccRCC tissues compared to healthy kidney tissue.
- E-cadherin expression is reduced in ccRCC and correlates with tumor stage and size.
- HIF-1α and HIF-3α levels are higher in pVHL-low tumors, while E-cadherin is negatively correlated with HIF-α expression.

## Abstract

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).

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).

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.

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.