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Pegylated interferon 2‐alpha mediated down‐regulation of Wnt/beta‐catenin pathway via up‐regulation of nuclear export factor RanBP3
Author(s) -
DAR MOHD JAMAL,
Thompson Michael D,
Monga Satdarshan
Publication year - 2010
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.24.1_supplement.354.10
Subject(s) - wnt signaling pathway , dkk1 , gene knockdown , wnt3a , beta catenin , interferon , chemistry , catenin , signal transduction , cancer research , microbiology and biotechnology , biology , immunology , biochemistry , gene
Pegylated‐Interferon‐α (Peg‐IFN) is widely used to treat chronic HCV infection and may have anti‐tumor properties. Wnt signaling pathway is hyperactive in a large proportion of Hepatocellular cancers (HCC). Here, we investigate the possibility that Peg‐IFN may act through inhibition of Wnt signaling. We exposed β‐catenin overexpressing mice to chemical carcinogen and began treatment 10 weeks later with Peg‐IFN (7,000 or 70,000 U) for six weeks. Livers isolated from these mice showed decreased nuclear β‐catenin and decreased Ki‐67 staining when compared to saline‐treated mice. However, no change in the β‐catenin gene transcription was observed. In order to understand the mechanism, we carried out in vitro studies on human hepatoma cells (HepG2 & Hep3B). Treatment with Peg‐IFN led to a decrease in the active form of β‐catenin in these cells. Likewise, β‐catenin‐dependent transcriptional activity was decreased by up to 50% as measured by a 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. Moreover, SiRNA mediated knockdown of RanBP3 ablated the negative effect of Peg‐IFN on β‐catenin transcriptional activity. In conclusion, Peg‐IFN effectively downregulates Wnt/β‐catenin signaling at least partly through expression of RanBP3, which might be a new target for treatment of β‐catenin associated HCC.