Immunohistochemical evaluation of Bcl-2 gene family expression in liver of hepatitis C and cirrhotic patients: a novel mechanism to explain the high incidence of hepatocarcinoma in cirrhotics.

Abstract

The purpose of this study was to determine whether there is an increase in expression of bcl-2 and related bcl-2 gene family members bcl-X and bax in liver biopsy samples obtained from patients with either hepatitis C infection or cirrhosis. Bcl-2, bcl-X, and bax, as well as other bcl-2-related proteins, function coordinately through homo- and heterodimerization to regulate apoptosis. Bcl-2, which is characterized as an antiapoptotic, also functions as an antioxidant. We hypothesized that a mechanism that could account for increased hepatocellular carcinoma in patients with hepatitis C and cirrhosis is selection of bcl-2 expressing cells. This selection would be due to the capacity of individual cells to resist the toxic effects of inflammatory byproducts, specifically reactive oxygen species. Sections cut from archived liver biopsy samples embedded in paraffin were probed with antibody specific for bcl-2, bcl-X, or bax. Liver samples were from normal (N = 5), hepatitis C patients (N = 19), and cirrhotics (N = 10). Percent positive staining and intensity of staining were judged independently for hepatocytes, bile ducts, mononuclear cells, and Kupffer cells. Bcl-2 expression was evident in bile ducts and mononuclear cells of hepatitis C patients, but was not commonly present in hepatocytes (two of 10). In the cirrhotic liver, bcl-2 expression was also detected in bile ducts and mononuclear cells, but in contrast to hepatitis patients was also expressed in hepatocytes (nine of 10). A similar pattern of expression was evident for bcl-X, but in general the level of expression was limited relative to that of bcl-2. Bax expression was infrequently present in sections from any of the three patient groups. The data indicate that bcl-2 expression is elevated in the liver of cirrhotics, but is not evident in the liver of hepatitis C patients. This increase in expression of bcl-2 in cirrhotic patients may correlate with development of hepatocellular carcinoma given the anti-apoptotic/oncogenic potential of bcl-2.