Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma

Mathieu Boissan, Eleonore Beurel, Dominique Wendum, Colette Rey, Yann Lécluse, Chantal Housset, Marie Lise Lacombe, Christèle Desbois-Mouthon

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

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-3β 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.

Original languageEnglish
Pages (from-to)869-877
Number of pages9
JournalAmerican Journal of Pathology
Volume167
Issue number3
StatePublished - Sep 1 2005
Externally publishedYes

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Insulin Receptor Substrate Proteins
Hepatocellular Carcinoma
Somatomedins
human IRS2 protein
Liver
Phosphatidylinositol 3-Kinase
Insulin
Apoptosis
Polyomavirus Transforming Antigens
Glycogen Synthase Kinase 3
Diethylnitrosamine
Viral Tumor Antigens

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Boissan, M., Beurel, E., Wendum, D., Rey, C., Lécluse, Y., Housset, C., ... Desbois-Mouthon, C. (2005). Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. American Journal of Pathology, 167(3), 869-877.

Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. / Boissan, Mathieu; Beurel, Eleonore; Wendum, Dominique; Rey, Colette; Lécluse, Yann; Housset, Chantal; Lacombe, Marie Lise; Desbois-Mouthon, Christèle.

In: American Journal of Pathology, Vol. 167, No. 3, 01.09.2005, p. 869-877.

Research output: Contribution to journalArticle

Boissan, M, Beurel, E, Wendum, D, Rey, C, Lécluse, Y, Housset, C, Lacombe, ML & Desbois-Mouthon, C 2005, 'Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma', American Journal of Pathology, vol. 167, no. 3, pp. 869-877.
Boissan M, Beurel E, Wendum D, Rey C, Lécluse Y, Housset C et al. Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. American Journal of Pathology. 2005 Sep 1;167(3):869-877.
Boissan, Mathieu ; Beurel, Eleonore ; Wendum, Dominique ; Rey, Colette ; Lécluse, Yann ; Housset, Chantal ; Lacombe, Marie Lise ; Desbois-Mouthon, Christèle. / Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. In: American Journal of Pathology. 2005 ; Vol. 167, No. 3. pp. 869-877.
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