Pegylated interferon alpha targets Wnt signaling by inducing nuclear export of β-catenin

Background 82 Aims: Pegylated-Interferon-alpha 2a (peg-IFN), a first line therapy for Hepatitis C virus (HCV) patients, also impacts the recurrence of hepatocellular carcinoma (HCC). The activation of the Wnt pathway due to p-catenin gene mutations contributes to the development of a significant subset of HCC. Herein, we explored the effect of peg-IFN on Wnt/beta-catenin signaling in vitro and in vivo. Methods: Multiple human hepatoma cell lines were treated with Peg-IFN to assess its effect on the Wnt pathway and the mechanisms involved. Transgenic (TG) mice expressing stable p-catenin mutant in the liver were exposed to diethylnitrosamine (DEN) and treated with peg-IFN. Results: In vitro, peg-IFN decreased the transcriptional activity of beta-catenin/Tcf and did so independently of JAK/Stat signaling. Peg-IFN treatment led to increased mRNA and protein expression of RanBP3, a known p-catenin nuclear export factor, in all hepatoma cells. Co-precipitation studies showed an increased association between RanBP3 and p-catenin after peg-IFN treatment. The siRNA-mediated RanBP3 knockdown abrogated Peg-IFN-induced decrease in TOPFlash reporter activity. In vivo, Peg-IFN treatment led to increased nuclear RanBP3, decreased nuclear p-catenin and cyclin D1, and decreased cytoplasmic glutamine synthetase. Increased association of RanBP3 and p-catenin was also observed in vivo in response to Peg-IFN that led to decreased hepatocyte proliferation. Conclusions: Peg-IFN inhibits p-catenin signaling through the up-regulation of RanBP3, which may be a contributory mechanism for the delayed HCC and improved survival in treated HCV patients. This observation might have chemo-preventive or chemo-therapeutic implications in tumor with aberrant Wnt pathway activation. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.