Regulation of insulin-like growth factor II gene expression by hepatitis B virus in hepatocellular carcinoma. 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-tumor-bearing 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 non-tumor-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 patch 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. 