Nucleoporin 88 expression in hepatitis B and C virus-related liver diseases

Abstract

Aim: To investigate the expression of nucleoporin 88 (Nup88) in hepatitis B virus (HBV) and C virus (HCV)-related liver diseases.

Methods: We generated a new monoclonal Nup88 antibody to investigate the Nup88 protein expression by immunohistochemistry (IHC) in 294 paraffin-embedded liver specimens comprising all stages of hepatocellular carcinogenesis. In addition, in cell culture experiments HBV-positive (HepG2.2.15 and HB611) and HBV-negative (HepG2) hepatoma cell lines were tested for the Nup88 expression by Western-immunoblotting to test data obtained by IHC.

Results: Specific Nup88 expression was found in chronic HCV hepatitis and unspecific chronic hepatitis, whereas no or very weak Nup88 expression was detected in normal liver. The Nup88 expression was markedly reduced or missing in mild chronic HBV infection and inversely correlated with HBcAg expression. Irrespective of the HBV- or HCV-status, increasing Nup88 expression was observed in cirrhosis and dysplastic nodules, and Nup88 was highly expressed in hepatocellular carcinomas. The intensity of Nup88 expression significantly increased during carcinogenesis (P<0.0001) and correlated with dedifferentiation (P<0.0001). Interestingly, Nup88 protein expression was significantly downregulated in HBV-positive HepG2.2.15 (P<0.002) and HB611 (P<0.001) cell lines as compared to HBV-negative HepG2 cells.

Conclusion: Based on our immunohistochemical data, HBV and HCV are unlikely to influence the expression of Nup88 in cirrhotic and neoplastic liver tissue, but point to an interaction of HBV with the nuclear pore in chronic hepatitis. The expression of Nup88 in nonneoplastic liver tissue might reflect enhanced metabolic activity of the liver tissue. Our data strongly indicate a dichotomous role for Nup88 in non-neoplastic and neoplastic conditions of the liver.

Figure 3

Nuclear Nup88-expression in a DN (A) and in dark brown nuclei of an undifferentiated HCC (B).

Figure 1

Nuclear Nup88 expression (brown nuclei) in non-neoplastic hepatocytes of a liver biopsy with mild unspecific chronic hepatitis (A), weak nuclear expression of Nup88 in chronic HBV-related hepatitis with mild inflammatory changes (B), and moderate nuclear expression of Nup88 in chronic HCV-related hepatitis with mild inflammatory changes (C).

Figure 2

Western blot analysis showing reduced expression of Nup88 in HBV-positive HepG2.2.15 cells (A) and increased Nup88 expression in HBV-negative HepG2 and HBV-positive HepG2.2.15 (P < 0.002) and HB611 (P < 0.001) cells (B).