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(American Journal of Pathology. 2005;167:869-877.)
© 2005 American Society for Investigative Pathology

Overexpression of Insulin Receptor Substrate-2 in Human and Murine Hepatocellular Carcinoma

Mathieu Boissan*, Eléonore Beurel*, Dominique Wendum{dagger}, Colette Rey*, Yann Lécluse{ddagger}, Chantal Housset*, Marie-Lise Lacombe* and Christèle Desbois-Mouthon*

From INSERM U.680,* Université Pierre et Marie Curie, Paris; the Laboratoire d’Anatomie Pathologique,{dagger} Hôpital Saint-Antoine, Paris; and the Service Commun de Cytométrie PR2,{ddagger} Institut Gustave Roussy, Villejuif, France

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-3ß 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.




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