Decreased expression of CHIP leads to increased angiogenesis via VEGF-VEGFR2 pathway and poor prognosis in human renal cell carcinoma

Abstract

CHIP (c-terminal Hsp70-interacting protein) is an E3 ligase which may play different roles in different cancers. The elucidation of the VHL-HIF-1α(hypoxia inducible factor-1α)-VEGF (vascular endothelial growth factor) pathway has led to the development of targeted therapy in renal cell carcinoma (RCC). However, little is known about the role of CHIP and the relationship between CHIP and VEGF-VEGFR2 (VEGF receptor 2) pathway in RCC. In this study, we found that the expression of CHIP was downregulated and significantly correlated with pT status (P = 0.022) and TNM stage (Pâ ‰=â ‰0.022) in 304 RCC and 35 normal renal tissues using tissue microarray. Moreover, low expression of CHIP is a strong and independent negative prognostic value for RCC. In vitro, CHIP negatively regulated RCC cell migration, invasion and angiogenesis. In addition, ELISA tests showed that restoration of CHIP inhibited, while knockdown promoted, the secreted level of VEGF. Furthermore, western blot indicated that the VEGFR2 protein level was reduced after CHIP overexpression. Our findings demonstrate for the first time that CHIP may be involved in RCC angiogenesis through regulating VEGF secretion and expression of VEGFR2. CHIP may serve as promising prognostic biomarker of angiogenesis and may constitute a potential therapeutic target in RCC.