Hepatitis C Virus Infection in Patients is Associated With C/ EBPβ-Thr266 Phosphorylation and Hepatocyte Proliferation

Abstract

AIM: Hepatitis C virus (HCV) infection in patients induces hepatocyte proliferation and also hepatocellular carcinoma. The mechanisms and the liver acinar distribution of the HCV infection remain unclear. The aim of this study was to determine the liver acinar localization of the infectious HCV and whether HCV infection is associated with the expression of proteins known to modulate hepatocyte proliferation. METHODS: We analyzed normal (n = 6), HCV genotype 1-infected non cirrhotic (n = 6) and HCV genotype 1-infected cirrhotic liver samples (n = 6). We performed immunofluorescent studies using antibodies against HCV Core, Glutamine synthetase (as a marker of hepatic acinar zone-3 in normal livers); phosphorylated C/EBPβ-Thr266 (since it is required for Transforming Growth Factorα-and Hepatic Growth Factor - induced hepatocyte proliferation) and ki-67 (as an indicator of hepatocyte proliferation). Also, we analyzed by QRT-PCR a proliferation microarray to compare the expression of genes associated with cell proliferation in HCV-infected patients. RESULTS: In patients with HCV infection, the HCV Core protein was preferentiallyco-localized with hepatocytes expressing Glutamine synthetase, phosphorylated C/EBPβ-Thr266, HIF-1α and β-Catenin. As expected, phosphorylated C/EBPβ-Thr266 was associated with hepatocyte proliferation in these patients. HCV infection markedly increased hepatocyte proliferation. CONCLUSION: This study demonstrates that HCV infection is preferentially localized to an expanded acinar zone expressing GS, where enhanced hepatocyte proliferation occurs in association with phosphorylated C/EBPβ-Thr266. A better understanding of the mechanisms of HCV infection may facilitate additional studies and potential therapeutic interventions.