CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer
CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer
复制标题
CHIP 作为一种新型肿瘤血管生成抑制剂，对人类胃癌具有预后意义
DOI：
10.1136/gutjnl-2011-301522
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发表时间：
2013-04-01
期刊：
影响因子：
24.5
通讯作者：
Zhou, Jianwei W.
中科院分区：
文献类型：
--
作者：
Wang, Shouyu;Wu, Xuming;Zhou, Jianwei W.
目的CHIP（carboxy-terminal of Hsc 70 interacting protein）是一种E3泛素连接酶，可诱导多种肿瘤相关蛋白的泛素化和降解，抑制肿瘤转移。本研究旨在探讨CHIP在胃癌中的生物学功能及其临床意义。方法采用组织芯片和免疫组化染色技术，在两个独立的人胃癌队列中评估CHIP表达的预后价值。在体外和体内测定CHIP对致瘤性和血管生成的作用。结果胃癌组织中CHIP的表达明显低于癌旁组织。低肿瘤CHIP表达与患者的临床病理特征显著相关，以及与两个队列中较短的总生存期相关。多因素考克斯回归分析显示CHIP表达是胃癌患者的独立预后因素。此外，CHIP过表达可抑制软琼脂中贴壁非依赖性集落的形成，抑制裸鼠移植瘤的生长，并通过抑制核因子κB（NF-κB）介导的白细胞介素8（IL-8）表达抑制内皮细胞的生长和管腔形成。体内研究还证实，CHIP抑制血管形成和CD 31阳性细胞在基质胶塞中的募集。CHIP还与NF-κB/p65相互作用，促进其泛素化和蛋白酶体降解，终止NF-κB活性，抑制IL-8诱导的血管生成，这与随后的肿瘤转移有关。结论胃癌组织中CHIP表达降低导致肿瘤血管生成增加，促进胃癌的进展和预后不良。CHIP表达是GC候选临床预后标志物和推定的治疗靶点。
Objective CHIP (carboxy terminus of Hsc70 interacting protein) is an E3 ubiquitin ligase that can induce ubiquitination and degradation of several tumour related proteins, and acts as a suppressor of tumour metastasis. This study explored the biological function and clinical significance of CHIP in gastric cancer (GC). Methods The prognostic value of CHIP expression was evaluated using tissue microarray and immunohistochemical staining in two independent human GC cohorts. The role of CHIP on tumorigenicity and angiogenesis was determined in vitro and in vivo. Results CHIP expression was significantly decreased in GC lesions compared with paired non-cancerous tissues. Low tumoral CHIP expression significantly correlated with clinicopathological characteristics in patients, as well as with shorter overall survival in both cohorts. Multivariate Cox regression analysis revealed that CHIP expression was an independent prognostic factor for human GC patients. Moreover, CHIP overexpression impeded the formation of anchorage independent colonies in soft agar, suppressed the growth of xenografts in nude mice and inhibited endothelial cell growth and tube formation by suppressing nuclear factor κB (NF-κB) mediated interleukin 8 (IL-8) expression in vitro. In vivo studies also confirmed that CHIP inhibited blood vessel formation and recruitment of CD31 positive cells in matrigel plugs. Also, CHIP interacted with NF-κB/p65 and promoted its ubiquitination and degradation by proteasome, terminating NF-κB activity and inhibiting IL-8-induced angiogenesis, which correlated with subsequent tumour metastasis. Conclusions Decreased CHIP expression in GC resulted in increased angiogenesis and contributed to GC progression and poor prognosis. CHIP expression is a GC candidate clinical prognostic marker and a putative treatment target.