OVEREXPRESSION OF INSULIN-RECEPTOR SUBSTRATE-1 EMERGES EARLY IN HEPATOCARCINOGENESIS AND ELICITS PRENEOPLASTIC HEPATIC GLYCOGENOSIS

Citation
D. Nehrbass et al., OVEREXPRESSION OF INSULIN-RECEPTOR SUBSTRATE-1 EMERGES EARLY IN HEPATOCARCINOGENESIS AND ELICITS PRENEOPLASTIC HEPATIC GLYCOGENOSIS, The American journal of pathology, 152(2), 1998, pp. 341-345
Citations number
25
Categorie Soggetti
Pathology
ISSN journal
00029440
Volume
152
Issue
2
Year of publication
1998
Pages
341 - 345
Database
ISI
SICI code
0002-9440(1998)152:2<341:OOISEE>2.0.ZU;2-#
Abstract
Insulin receptor substrate-1 (IRS-1) is a multisite docking protein oc cupying a central position in signaling cascades stimulated by a numbe r of growth factors including insulin, Using Western blotting and immu nohistochemistry, we investigated the expression of IRS-1 in more than 400 preneoplastic foci of altered hepatocytes and in 12 hepatocellula r carcinomas induced in rats by oral administration of N-nitrosomorpho line. In both N-nitrosomorpholine-treated and untreated rat livers, IR S-1 was demonstrable by Western blotting, but with the exception of a few single hepatocytes it was not detectable in the normal parenchyma by immunohistochemistry, In contrast, immunohistochemistry revealed th at IRS-1 was strongly expressed in the majority of foci of altered hep atocytes particularly in approximately 97% of the clear/acidophilic an d mixed cell foci showing excessive storage of glycogen (glycogenosis) . In glycogen-poor basophilic foci of altered hepatocytes and hepatoce llular carcinomas, IRS-1 was not detected by immunohistochemistry, but a weak expression was observed in small subpopulations of three hepat ocellular carcinomas containing remnants of glycogen. These results in dicate that the focal overexpression of IRS-1 is an early event in hep atocarcinogenesis, which is closely correlated with preneoplastic hepa tic glycogenosis. During progression from glycogenotic foci to hepatoc ellular carcinomas, IRS-1-overexpression is gradually down-regulated, and this late event is associated with a fundamental metabolic shift l eading to the malignant neoplastic phenotype.