title: Upregulation of the insulin receptor and type I insulin-like growth factor receptor are early events in hepatocarcinogenesis.
abstract: The molecular mechanisms underlying the development of hepatocellular carcinoma (HCC) are not yet fully understood. Preneoplastic foci of altered hepatocytes regularly precede HCC in various species. The predominant earliest type of foci of altered hepatocytes, the glycogen storage focus (GSF), shows an excess of glycogen (glycogenosis) in the cytoplasm. During progression from GSF to HCC, the stored glycogen is gradually reduced, resulting in complete loss in basophilic HCC. We have previously shown that in N-nitrosomorpholine-induced hepatocarcinogenesis, insulin receptor substrate (IRS-1) is strongly expressed in GSF and reduced during progression to HCC, thus correlating with the glycogen content. In the present study, we observed increased levels of insulin receptor, IGF-I receptor (IGF-IR), IRS-2, and mitogen-activated kinase/extracellular regulated kinase-1 in GSF, following the same pattern of expression as IRS-1. We conclude that the abundance of IRS-1, IRS-2, and mitogen-activated kinase/extracellular regulated kinase-1 coincides with a concerted upregulation of both IR and IGF-IR induced by the hepatocarcinogen. Our data suggest that in early hepatocellular preneoplasia, the upregulation of IR elicits glycogenosis through IRS-1 and/or IRS-2, whereas the increased level of the IGF-IR may lead to the increased cell proliferation previously reported in GSF. Therefore, the concerted upregulation of both IR and IGF-IR may represent initial events in hepatocarcinogenesis.
authors.affiliation: German Cancer Research Center, Cell Pathology Division, Heidelberg, Germany.
authors.forename: Eiman
authors.initials: E
authors.lastname: Aleem
authors.forename: Dirk
authors.initials: D
authors.lastname: Nehrbass
authors.forename: Fritz
authors.initials: F
authors.lastname: Klimek
authors.forename: Doris
authors.initials: D
authors.lastname: Mayer
authors.forename: Peter
authors.initials: P
authors.lastname: Bannasch
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006003:Glycogen / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008297:Male; D009602:Nitrosamines / Q000378:metabolism; D011230:Precancerous Conditions; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526299:Irs2 protein, rat; D009602:Nitrosamines; C002741:N-nitrosomorpholine; D006003:Glycogen; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D048369:MAP Kinase Kinase 1