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Pegylated interferon‐alpha targets beta‐catenin by inducing its nuclear export
Author(s) -
Thompson Michael D,
Monga Satdarshan S
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.438.3
Subject(s) - wnt signaling pathway , dkk1 , wnt3a , in vivo , beta catenin , luciferase , chemistry , interferon , catenin , signal transduction , cancer research , in vitro , microbiology and biotechnology , biology , immunology , transfection , biochemistry , gene
Treatment with Peg‐IFN, a first line therapy for chronic HCV infection, reduces the development of hepatocellular carcinoma (HCC). Furthermore, activation of the Wnt pathway is observed in a significant subset of HCC. We explored the possibility that Peg‐IFN may act through inhibition of Wnt signaling. To examine Peg‐IFN's effects in vivo, mice overexpressing β‐catenin were exposed to DEN and treated with Peg‐IFN (70,000 U) for six weeks. Treatment with Peg‐IFN decreased nuclear β‐catenin compared to saline treated and decreased Ki‐67 positive hepatocytes. No change in the transcription of β‐catenin was evident suggesting the effect to be through a post‐translational mechanism. We began in vitro studies to verify this finding and explore the mechanism of reduced Wnt signaling. Treatment of human hepatoma cells (HepG2 & Hep3B) with Peg‐IFN led to a decrease in the active form of β‐catenin. Likewise, β‐catenin dependent transcriptional activity was decreased by up to 50% as measured by TOPflash luciferase reporter assay. Real‐time PCR showed an increase in two negative regulators of Wnt signaling, Dkk1 and RanBP3. Overexpression of RanBP3 in HepG2 cells significantly decreased β‐catenin transcriptional activity. Thus Peg‐IFN effectively downregulates Wnt/β‐catenin signaling at least partly through increased expression of RanBP3, which is an attractive means of therapeutically inhibiting mutated‐β ‐catenin.