Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma
Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma
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DOI：
10.1016/s0002-9440(10)62058-5
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发表时间：
2005-09-01
影响因子：
6
通讯作者：
Desbois-Mouthon, C
中科院分区：
文献类型：
--
作者：
Boissan, M;Beurel, E;Desbois-Mouthon, C
胰岛素和胰岛素样生长因子（IGF）途径的失调可能有助于肝细胞癌。虽然细胞内胰岛素受体底物-2（IRS-2）是肝脏胰岛素信号传导的主要效应物，但其在肝癌发生中的作用尚不清楚。在这里，我们发现IRS-2在两种小鼠肝癌模型中过表达：二乙基亚硝胺和SV 40大T抗原的肝脏过表达。在这两种模型中，IRS-2的过度表达在癌前病变中检测到，在肿瘤结节中检测到更高的水平。IRS-2过表达与IGF-2和IRS-1过表达以及GSK-3 β抑制相关。IRS-2在人肝细胞癌标本和肝癌细胞系中的表达也有增加。在小鼠和人肝癌细胞中，IRS-2蛋白诱导与IRS-2 mRNA水平增加相关。IRS-2的功能在Hep 3B细胞中得到证实，其中IRS-2酪氨酸磷酸化及其与磷脂酰肌醇-3激酶的结合被IGF-2诱导。此外，IRS-2表达的下调增加了这些细胞的凋亡。总之，我们证明IRS-2在人类和小鼠肝细胞癌中过表达。IRS-2在实验性肝癌发生过程中癌前阶段的过度表达及其对细胞凋亡的保护作用表明IRS-2有助于肝脏肿瘤的进展。
Deregulations in insulin and insulin-like growth factor (IGF) pathways may contribute to hepatocellular carcinoma. Although intracellular insulin receptor substrate-2 (IRS-2) is the main effector of insulin signaling in the liver, its role in hepatocarcinogenesis is unknown. Here, we show that IRS-2 was overexpressed in two murine models of hepatocarcinogenesis: administration of diethylnitrosamine and hepatic overexpression of SV40 large T antigen. In both models, IRS-2 overexpression was detected in preneoplastic lesions and at higher levels in tumoral nodules. IRS-2 overexpression associated with IGF-2 and IRS-1 overexpression and with GSK-3 beta inhibition. Increased expression of IRS-2 was also detected in human hepatocellular carcinoma specimens and hepatoma cell lines. In murine and human hepatoma cells, IRS-2 protein induction associated with increased IRS-2 mRNA levels. The functionality of IRS-2 was demonstrated in Hep3B cells, in which IRS-2 tyrosine phosphorylation and its association with phosphatidylinositol-3 kinase were induced by IGF-2. Moreover, down-regulation of IRS-2 expression increased apoptosis in these cells. In conclusion, we demonstrate that IRS-2 is overexpressed in human and murine hepatocellular carcinoma. The emergence of IRS-2 overexpression at preneoplastic stages during experimental hepatocarcinogenesis and its protective effect against apoptosis suggest that IRS-2 contributes to liver tumor progression.