RGD Reference Report - Insulin receptor, insulin receptor substrate-1, Raf-1, and Mek-1 during hormonal hepatocarcinogenesis by intrahepatic pancreatic islet transplantation in diabetic rats. - Rat Genome Database

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Insulin receptor, insulin receptor substrate-1, Raf-1, and Mek-1 during hormonal hepatocarcinogenesis by intrahepatic pancreatic islet transplantation in diabetic rats.

Authors: Evert, M  Sun, J  Pichler, S  Slavova, N  Schneider-Stock, R  Dombrowski, F 
Citation: Evert M, etal., Cancer Res. 2004 Nov 1;64(21):8093-100.
RGD ID: 2306052
Pubmed: PMID:15520221   (View Abstract at PubMed)
DOI: DOI:10.1158/0008-5472.CAN-04-2040   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
INSRHumanExperimental Liver Neoplasms disease_progressionISOInsr (Rattus norvegicus)associated with Diabetes Mellitus more ...RGD 
InsrRatExperimental Liver Neoplasms disease_progressionIEP associated with Diabetes Mellitus more ...RGD 
InsrMouseExperimental Liver Neoplasms disease_progressionISOInsr (Rattus norvegicus)associated with Diabetes Mellitus more ...RGD 
MAP2K1HumanExperimental Liver Neoplasms  ISOMap2k1 (Rattus norvegicus)associated with Diabetes Mellitus more ...RGD 
Map2k1RatExperimental Liver Neoplasms  IEP associated with Diabetes Mellitus more ...RGD 
Map2k1MouseExperimental Liver Neoplasms  ISOMap2k1 (Rattus norvegicus)associated with Diabetes Mellitus more ...RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
InsrRatinsulin receptor signaling pathway  IEP  RGD 
InsrRatresponse to nutrient levels  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Insr  (insulin receptor)
Map2k1  (mitogen activated protein kinase kinase 1)

Genes (Mus musculus)
Insr  (insulin receptor)
Map2k1  (mitogen-activated protein kinase kinase 1)

Genes (Homo sapiens)
INSR  (insulin receptor)
MAP2K1  (mitogen-activated protein kinase kinase 1)


Additional Information