Insulin receptor substrate-1 is over-expressed in glycogenotic but not in amphophilic preneoplastic hepatic foci induced in rats by N-nitrosomorpholine and dehydroepiandrosterone.
Insulin receptor substrate-1 (IRS-1) is over-expressed in preneoplastic glycogenotic hepatic foci (GSF) and is gradually down-regulated during progression of these lesions, via mixed cell foci (MCF), to the basophilic neoplastic phenotype. The aim of the present study was to investigate the effect of dehydroepiandrosterone (DHEA), a weak hepatocarcinogen and tumour enhancer, on IRS-1 expression. Hepatocellular lesions were induced by N-nitrosomorpholine followed by DHEA. Under these conditions, many glycogen-poor amphophilic (APF) and intermediate cell foci (ICF) appear, in addition to GSF and MCF. IRS-1 was over-expressed in 215 out of 295 GSF, in 50 out of 53 MCF and in a glycogen-rich mixed cell adenoma. IRS-1 expression was not shown in 147 APF, 51 ICF and 5 amphophilic hepatocellular adenomas, and 3 out of 5 hepatocellular carcinomas showed a weak IRS-1 expression. The results suggest a close association of IRS-1 over-expression with the glycogenotic hepatocellular phenotype. The modulation and enhancement of tumour progression by DHEA is associated with a shift from glycogenosis to amphophilia and basophilia, and a down-regulation of IRS-1 expression.
Abteilung für Cytopathologie, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
D
D
Nehrbass
F
F
Klimek
P
P
Bannasch
D
D
Mayer
D018248:Adenoma, Liver Cell / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism*; D003687:Dehydroepiandrosterone; D005260:Female; D006003:Glycogen / Q000378:metabolism*; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism*; D009602:Nitrosamines; D010750:Phosphoproteins / Q000096:biosynthesis*; D011230:Precancerous Conditions / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D009602:Nitrosamines; D010750:Phosphoproteins; C002741:N-nitrosomorpholine; D003687:Dehydroepiandrosterone; D006003:Glycogen