Decreased expression of CHIP leads to increased angiogenesis via VEGF-VEGFR2 pathway and poor prognosis in human renal cell carcinoma.
Decreased expression of CHIP leads to increased angiogenesis via VEGF-VEGFR2 pathway and poor prognosis in human renal cell carcinoma.
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CHIP 表达减少导致人肾细胞癌中通过 VEGF-VEGFR2 途径的血管生成增加和预后不良
DOI：
10.1038/srep09774
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发表时间：
2015-05-29
影响因子：
4.6
通讯作者：
Zheng JN
中科院分区：
文献类型：
--
作者：
Sun C;Li HL;Chen HR;Shi ML;Liu QH;Pan ZQ;Bai J;Zheng JN
CHIP（c-terminal Hsp 70-interacting protein）是一种E3连接酶，在不同的癌症中可能发挥不同的作用。VHL-HIF-1α（hypoxia inducible factor-1α）-VEGF（vascular endothelial growth factor）信号通路的发现，促进了肾细胞癌（renal cell carcinoma，RCC）靶向治疗的发展。然而，关于CHIP在RCC中的作用以及CHIP与VEGF-VEGFR 2（VEGF受体2）通路之间的关系，人们知之甚少。本研究采用组织芯片技术检测了304例肾癌组织和35例正常肾组织中CHIP的表达，发现CHIP的表达与pT状态（P = 0.022）和TNM分期（P = 0.022）显著相关。此外，CHIP的低表达是肾癌的一个强而独立的负预后价值。在体外，CHIP负调控RCC细胞的迁移、侵袭和血管生成。此外，ELISA试验表明，CHIP的恢复抑制，而敲低促进，VEGF的分泌水平。Western blot结果显示，CHIP过表达后VEGFR 2蛋白水平降低。我们的研究结果首次证明，CHIP可能通过调节VEGF的分泌和VEGFR 2的表达参与RCC血管生成。CHIP可能作为一个有前途的预后血管生成的生物标志物，并可能构成一个潜在的治疗肾癌的目标。
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 (P = 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.
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