Gene expression regulation for interferon-alpha in hepatocellular carcinoma.

We investigated whether regulation of interferon-alpha gene expression could be involved in liver tumor biology and the role, if any, of hepatitis B virus in the regulation of tumor cytokine gene expression. Gene expression was investigated at the transcriptional level using 'in situ' hybridization of cytokine message with an interferon-alpha cDNA probe and at the translational level with immunohistochemistry using an immunoperoxidase technique. Compared to histologically normal liver, a greater percentage of tumor and non-tumor-involved liver tissue sections (67-80% vs. 17%) contained cells positive for interferon-alpha messenger RNA, many of which were also seen to contain an increased number of transcripts (> 100 grains/cell). Hepatitis B infection did not appear to play a role in gene activation, at the hepatocellular level, in liver disease. Except for sinusoidal cells, cells containing cytokine transcripts also produced mature immunoreactive protein. Absence of interferon-alpha protein within mononuclear and sinusoidal cells in seronegative hepatocellular carcinoma tissue with/without underlying liver disease suggested deficient cytokine gene expression, at the post transcriptional level, within these cells in this group. Bile duct epithelia in tumor tissue were found to contain immunoreactive protein for interferon-alpha. In summary our results suggest that interferon-alpha gene activation in hepatocellular carcinoma occurs as a result of the liver cell damage and does not play a dominant role in tumor biology.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth factors, endocrine aspects and hormonal treatment in hepatocellular carcinoma--an overview.

Several clinical observations suggest that hepatocellular carcinoma (HCC or "hepatoma") may be a hormone-dependent tumour; the apparent relation to anabolic steroids and oral contraceptive preparations, and the striking male predominance particularly among patients with cirrhosis. In many animal models thyroid hormones, prolactin and testosterone stimulate tumour growth, and the latter may enhance the progression of chemically-induced hyperplastic nodules to frank malignancy. In animals and humans, both oestrogen and androgen receptors have been reported in normal and malignant liver tissue though some of the evidence is conflicting and the amounts detected vary widely. From a therapeutic standpoint, we failed to show any advantage from the addition of tamoxifen to adriamycin, in a controlled trial although other workers have, more recently, reported prolonged survival using tamoxifen alone. About 20% of HCC patients receiving the antiandrogen cyproterone acetate showed a clinical response.

Alterations in the functional expression of receptors on cirrhotic rat hepatocytes.

Reduced hepatic uptake and clearance of macromolecules in liver cirrhosis is due to two major factors: increased diffusional barriers, resulting primarily from the deposition of excessive connective tissue in the space of Disse, and hepatocellular dysfunction, manifested by receptor and/or postreceptor defects. To probe the mechanisms underlying hepatocellular dysfunction in liver cirrhosis, we have investigated receptor-ligand interactions for asialoorosomucoid, insulin and epidermal growth factor in hepatocytes isolated from the livers of rats chronically exposed to phenobarbital and carbon tetrachloride for up to 12 weeks. Viable cells were allowed to attach at 37 degrees C and the high-affinity cell surface binding sites for each ligand were assessed at 4 degrees C in the presence of [125I]-ligand. In parallel incubations, digitonin (0.055%) was added to the binding medium to assess total cellular binding sites. Results demonstrated that chronic treatment of rats with phenobarbital increased hepatocyte asialoorosomucoid surface receptor affinity (p less than 0.05) but had no affect on the number of asialoglycoprotein binding sites. Treatment with CCl4 and phenobarbital significantly reduced the number of surface binding sites for asialoorosomucoid (p less than 0.05) and epidermal growth factor (p less than 0.02), although this treatment had no effect on either the binding affinity or the number of binding sites for insulin. The decrease in cell surface binding sites for asialoorosomucoid and epidermal growth factor was not due to a redistribution of the surface sites to intracellular locations, since the total number of cellular binding sites also was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)