TY - JOUR
T1 - Pegylated interferon alpha targets Wnt signaling by inducing nuclear export of β-catenin
AU - Thompson, Michael D.
AU - Dar, Mohd Jamal
AU - Monga, Satdarshan P.S.
N1 - Funding Information:
Financial support: This study was funded by NIH Grants 1R01DK62277 and 1R01CA124414 to S.P.S.M., 1F30DK083235 to M.D.T., and by Rango’s Fund for the Enhancement of Pathology Research . This project was also partly sponsored by Roche Pharmaceuticals , Grant Number PEG157 to S.P.S.M.
PY - 2011/3
Y1 - 2011/3
N2 - Background & Aims: 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.
AB - Background & Aims: 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.
KW - Hepatocellular cancer
KW - Interferon
KW - Liver cancer
KW - Proliferation
KW - Ran binding protein-3 (RanBP3)
KW - Treatment
KW - Wnt
UR - http://www.scopus.com/inward/record.url?scp=79951670840&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2010.07.020
DO - 10.1016/j.jhep.2010.07.020
M3 - Article
C2 - 21093092
AN - SCOPUS:79951670840
SN - 0168-8278
VL - 54
SP - 506
EP - 512
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 3
ER -