title: Pegylated interferon alpha targets Wnt signaling by inducing nuclear export of β-catenin.
abstract: OBJECTIVE
  Pegylated-Interferon-α2a (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 β-catenin gene mutations contributes to the development of a significant subset of HCC. Herein, we explored the effect of peg-IFN on Wnt/β-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 β-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 β-catenin/Tcf and did so independently of JAK/Stat signaling. Peg-IFN treatment led to increased mRNA and protein expression of RanBP3, a known β-catenin nuclear export factor, in all hepatoma cells. Co-precipitation studies showed an increased association between RanBP3 and β-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 β-catenin and cyclin D1, and decreased cytoplasmic glutamine synthetase. Increased association of RanBP3 and β-catenin was also observed in vivo in response to Peg-IFN that led to decreased hepatocyte proliferation.
  
  
  CONCLUSIONS
  Peg-IFN inhibits β-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.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Thompson
authors.forename: Mohd Jamal
authors.initials: MJ
authors.lastname: Dar
authors.forename: Satdarshan P S
authors.initials: SP
authors.lastname: Monga
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D050505:Mutant Proteins; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; C112820:RANBP3 protein, human; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a