Regulation of insulin-like growth factor II gene expression by hepatitis B virus in hepatocellular carcinoma

Abstract

In this study we investigated the regulation of insulin-like growth factor II gene expression to explain a role for this growth factor in concert with hepatitis B virus involvement in the development of hepatocellular carcinoma from cirrhosis. Sections of normal liver and tumor and non-tumorbearing liver disease tissue were hybridized in situ with [35S]-labeled insulin-like growth factor II oligonucleotide probe. Parallel sections were tested for presence of insulin-like growth factor II polypeptide using immunohistochemistry. To investigate a possible role for hepatitis B virus in insulin-like growth factor II gene expression in hepatocellular carcinoma, results were analyzed against patient seropositivity for hepatitis B virus. Levels of insulin-like growth factor II transcripts in normal liver (n = 4) sections and in those from nontumor-bearing individuals (n = 10) were so low that specific signal was not detectable above homogeneous tissue background. In contrast, 4 of 8 (50%) of the sections of hepatocellular carcinoma arising from cirrhosis or noncirrhotic chronic liver disease with hepatitis B virus involvement showed increased expression of insulin-like growth factor II messenger RNA transcripts. Up-regulation was observed in cell foci in the hepatocellular regions of the surrounding cirrhotic lobular cells and the fibrous septa. Numerous cell foci were observed in patchy distribution in the tumor areas. The level of insulin-like growth factor II messenger RNA transcripts in sections of hepatocellular carcinoma arising from cirrhotic and noncirrhotic tissues obtained from patients seronegative for hepatitis B virus was similar to that of normal liver. Immunohistochemical study demonstrated that similar cells in the cirrhotic liver lobules containing insulin-like growth factor II messenger RNA transcripts also contained immunoreactive polypeptide. In contrast, we saw no positive staining for insulin-like growth factor II in tumor cells. These results imply a role for insulin-like growth factor II in the pathogenesis of cirrhotic/noncirrhotic chronic liver disease to hepatocellular carcinoma where there is evidence of hepatitis B virus involvement. Alterations in posttranscriptional events for insulin-like growth factor II in tumor cells may contribute to the maintenance or progression of the malignant phenotype. (HEPATOLOGY 1991;13:310–315).