Insulin receptor, insulin receptor substrate-1, Raf-1, and Mek-1 during hormonal hepatocarcinogenesis by intrahepatic pancreatic islet transplantation in diabetic rats.
Low-number transplantation of pancreatic islets into the livers of diabetic rats leads to transformation of the downstream liver acini into clear-cell foci of altered hepatocytes (FAHs). These FAHs correspond to the glycogen-storing (clear-cell) phenotype of hepatocellular preneoplasias and develop into hepatocellular adenomas (HCAs) and hepatocellular carcinomas (HCCs) within 6 to 24 months. In addition, they show metabolic alterations that resemble well-known insulin effects, most likely constituting the result of the local hyperinsulinemia. Thus, we investigated FAHs, HCAs, and HCCs for altered expression of insulin receptor, insulin receptor substrate-1 (IRS-1), Raf-1 and Mek-1. Light and electron microscopic immunohistochemistry revealed a translocation of insulin receptor from the plasma membrane (normal tissue) into the cytoplasm in clear-cell FAHs and an increase in insulin receptor expression in HCAs and HCCs. FAHs also showed an increase in IRS-1 gene expression, investigated by in situ hybridization and quantitative reverse transcription-PCR. IRS-1, Raf-1, and Mek-1 proteins were strongly overexpressed in FAHs and tumors, as compared with the unaltered liver tissue. These overexpressions were closely linked to the clear-cell phenotype of preneoplastic and neoplastic hepatocytes, because basophilic FAHs (later stages) and basophilic tumors showed no overexpressions. In this endocrine model of hepatocarcinogenesis, severe alterations of insulin signaling were induced by the pathological local action of islet hormones in the livers and may substantially contribute to the carcinogenic process.
Evert
Matthias
M
Institut für Pathologie der Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany.
Sun
Jianping
J
Pichler
Sabine
S
Slavova
Nadia
N
Schneider-Stock
Regine
R
Dombrowski
Frank
F
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D055504:Insulin Receptor Substrate Proteins; D016381:Islets of Langerhans Transplantation; D008114:Liver Neoplasms, Experimental / Q000209:etiology*; D048369:MAP Kinase Kinase 1 / Q000032:analysis / Q000502:physiology*; D008297:Male; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011230:Precancerous Conditions / Q000209:etiology*; D019908:Proto-Oncogene Proteins c-raf / Q000032:analysis / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D011972:Receptor, Insulin / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction; D013311:Streptozocin
D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D012333:RNA, Messenger; D013311:Streptozocin; D011972:Receptor, Insulin; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human