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
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.