Oncogenic role of the frizzled-7/β-catenin pathway in hepatocellular carcinoma

Background/Aims The molecular mechanisms of hepatocarcinogenesis remain largely unknown. Previous studies suggest that activation of the Wnt/β-catenin pathway is important during hepatocyte transformation but the role of Frizzled receptor (FZD) in this process has not been defined. Here we investigate activation of this pathway by FZD using transgenic hepatocellular carcinoma (HCC) murine models. Methods We employed single (c-myc, SV40-Tag) and established double [insulin receptor substrate-1 (IRS-1/c-myc) and hepatitis Bx protein (X/c-myc)] transgenic lines and all developed HCC. Expression of 9 FZD was measured by real time RT-PCR and Western blot analysis. Phosphorylation and cellular accumulation of β-catenin were assessed in both dysplastic tissue and tumors. We investigated the effect of a dominant negative (DN) FZD7 on TCF transcriptional activity in a SV40 derived HCC cell line. Results FZD7 was highly overexpressed at the mRNA and protein level(s) in HCC and occurred in dysplasia. Upregulation of FZD7 was associated with reduced phosphorylation of β-catenin and led to nuclear accumulation in HCC tumors. Ectopic expression of a DN FZD7 construct decreased TCF transcriptional activity in tumor cells. Conclusions These observations suggest that upregulation of FZD7 receptors in association with activation of the canonical Wnt/β-catenin pathway is a common molecular event in HCC.