Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma.
De-regulations 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-3beta 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 Hep 3 B 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.
Boissan
Mathieu
M
INSERM U.680, Universitié Pierre et Marie Curie, Paris, France.
Beurel
Eléonore
E
Wendum
Dominique
D
Rey
Colette
C
Lécluse
Yann
Y
Housset
Chantal
C
Lacombe
Marie-Lise
ML
Desbois-Mouthon
Christèle
C
D000477:Alkylating Agents; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004052:Diethylnitrosamine; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010750:Phosphoproteins / Q000378:metabolism*; D013997:Time Factors
D000477:Alkylating Agents; D000952:Antigens, Polyomavirus Transforming; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D004052:Diethylnitrosamine