Focal overexpression of insulin-like growth factor 2 by hepatocytes and cholangiocytes in viral liver cirrhosis.
Insulin-like growth factor (IGF)-2 is overexpressed in hepatocellular carcinoma and accompanying dysplastic lesions. IGF-2 signalling is mediated through IGF-1 receptor (IGF-1R), while mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF-2R) controls pericellular levels of free IGF-2. We studied, by in situ hybridisation and immunohistology, 18 liver specimens with cirrhosis of different aetiology without neoplastic or dysplastic lesions. Immunohistology was also performed for insulin receptor IGF-1R and IGF-binding proteins 3 and 4. High focal levels of IGF-2 RNA were found in some hepatocytes of all livers with HBV- or HCV-induced cirrhosis (n=10), but in only one of the cirrhoses with nonviral aetiology (n=8). IGF-2 was overexpressed in biliary duct epithelial cells in one case. Compared with noncirrhotic liver, all cirrhotic specimens showed reduced hepatocellular expression of M6P/IGF-2R protein, which contrasted with enhanced expression in perisinusoidal cells. Immunostaining for the other antigens did not reveal significant differences. Upregulation of IGF-2 in some hepatocytes may lead to high focal IGF-2 levels sufficient to saturate local IGF-2 binding capacities, and may result in an increased susceptibility to cellular dedifferentiation and, ultimately, liver cancer. Downregulation of hepatocellular M6P/IGF-2R and upregulation of IGF-2 seem to be early events in hepatocarcinogenesis prior to the appearance of morphologically distinct dysplastic lesions. Elevated focal IGF-2 transcript levels may therefore indicate an increased risk for hepatocellular and cholangiocellular carcinomas.
Sedlaczek
N
N
Institute of Pathology, University of Muenster, Germany.
Hasilik
A
A
Neuhaus
P
P
Schuppan
D
D
Herbst
H
H
D001652:Bile Ducts / Q000378:metabolism* / Q000473:pathology; D006525:Hepatitis, Viral, Human / Q000150:complications*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism*
D007335:Insulin-Like Growth Factor II