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

Published

Journal Article

BACKGROUND/AIMS: The molecular mechanisms of hepatocarcinogenesis remain largely unknown. Previous studies suggest that activation of the Wnt/beta-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 beta-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 beta-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/beta-catenin pathway is a common molecular event in HCC.

Full Text

Duke Authors

Cited Authors

  • Merle, P; Kim, M; Herrmann, M; Gupte, A; Lefrançois, L; Califano, S; Trépo, C; Tanaka, S; Vitvitski, L; de la Monte, S; Wands, JR

Published Date

  • November 2005

Published In

Volume / Issue

  • 43 / 5

Start / End Page

  • 854 - 862

PubMed ID

  • 16098625

Pubmed Central ID

  • 16098625

International Standard Serial Number (ISSN)

  • 0168-8278

Digital Object Identifier (DOI)

  • 10.1016/j.jhep.2005.05.018

Language

  • eng

Conference Location

  • Netherlands