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Pegylated‐Interferon 2α (Peg‐IFN) suppresses β‐catenin signaling in liver

Peg‐IFN is an effective first line therapy in treatment of chronic Hepatitis C virus (HCV) infection. Interestingly, HCV patients treated with Peg‐IFN are less likely to develop hepatocellular carcinoma (HCC). HCC remains the most common form of liver cancer and activation of the Wnt pathway is observed in a significant subset. We explored the possibility that Peg‐IFN may act through inhibition of Wnt signaling. Treatment of 2 human hepatoma cell lines (HepG2 & Hep3B) with various concentrations of 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 the TOPFLASH luciferase reporter assay. To examine Peg‐IFN.s effects in vivo, transgenic mice overexpressing a stabilized, mutant form of β‐catenin were exposed to DEN and treated with Peg‐IFN (7,000 or 70,000 U) for six weeks. Treatment with Peg‐IFN decreased nuclear β‐catenin compared to control. This was associated with a decrease in Ki‐67 positive hepatocytes. No change in the transcription of β‐catenin was evident suggesting the effect to be through a post‐ translational mechanism. Thus Peg‐IFN effectively downregulates Wnt/β‐catenin signaling and might have important treatment implications in HCC.