HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma
HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma
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DOI：
10.1038/labinvest.2010.136
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发表时间：
2011-01-01
影响因子：
5
通讯作者：
Al-Kuraya, Khawla S.
中科院分区：
文献类型：
--
作者：
Bu, Rong;Uddin, Shahab;Al-Kuraya, Khawla S.
Met受体酪氨酸激酶及其配体肝细胞生长因子（HGF）在多种人类恶性肿瘤中过度表达和/或被激活。然而，其在上皮性卵巢癌（EOC）中的作用尚未清楚阐明。因此，我们研究了HGF/c-Met信号通路在大量（156）沙特EOC患者样本、细胞系面板和裸鼠模型异种移植物中的作用。免疫组化结果显示，27.2%的中东EOC样本中c-Met过表达，且与肿瘤晚期相关（P = 0.0187）。c-Met过表达还与抗凋亡标志物x染色体相关凋亡抑制剂（XIAP） （P = 0.0008）和Bcl-XL （P = 0.0493）表达相关。用PHA665752处理EOC细胞系可引起剂量依赖性的细胞活力抑制和诱导凋亡。此外，PHA665752处理导致AKT的去磷酸化和抗凋亡蛋白XIAP和Bcl-XL的下调。此外，pha665752通过激活bax介导的细胞色素c的释放和caspases的激活来诱导细胞凋亡。最后，PHA665752与顺铂共处理EOC可增强EOC细胞凋亡，协同抑制裸鼠EOC异种移植瘤生长。这些结果表明，c-Met/HGF通路可能是EOC治疗干预的潜在靶点。实验室调查（2011）91,124-137；doi: 10.1038 / labinvest.2010.136;2010年7月26日在线发布
The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a variety of human malignancies. However, its role in epithelial ovarian carcinoma (EOC) has not been clearly elucidated. Therefore, we investigated the role of HGF/c-Met signaling pathway in a large series (156) of Saudi EOC patient samples, a panel of cell lines, and xenografts in a NUDE mouse model. Using immunohistochemistry, c-Met overexpression was found in 27.2% Middle Eastern EOC samples and was associated with an advanced tumor stage (P = 0.0187). c-Met overexpression was also associated with antiapoptotic markers X-chromosome-linked inhibitors of apoptosis (XIAP) (P = 0.0008) and Bcl-XL (P = 0.0493) expression. Treatment of EOC cell lines with PHA665752 causes a dose-dependent inhibition of cell viability and induction of apoptosis. Furthermore, PHA665752 treatment causes dephosphorylation of AKT and downregulation of antiapoptotic proteins XIAP and Bcl-XL. In addition, PHA665752-induced apoptosis occurs through activation of Bax-mediated release of cytochrome c and activation of caspases. Finally, co-treatment of EOC with PHA665752 and cisplatin causes augmented effect on apoptosis of EOC cells and resulted in synergistic inhibition of EOC xenograft tumor growth in NUDE mice. These results indicate that c-Met/HGF pathway may be a potential target for therapeutic intervention for treatment of EOC. Laboratory Investigation (2011) 91, 124-137; doi:10.1038/labinvest.2010.136; published online 26 July 2010