Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma

Gastroenterology. 2004 Oct;127(4):1110-22. doi: 10.1053/j.gastro.2004.07.009.


Background & aims: The molecular pathogenesis of human hepatocellular carcinoma (HCC) is understood poorly. In some tumors, activation of the Wnt/beta-catenin pathway as a result of beta-catenin gene mutations has been found. However, in many other HCCs, activation of the Wnt/beta-catenin pathway has been shown in the absence of such mutations.

Methods: We previously have identified the upstream human Frizzled-7 receptor (FZD7) gene of this pathway. In the present study, a quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) assay for FZD7 was developed and overexpression of FZD7 was detected in 90% of tumors, most of which were related to chronic hepatitis B virus infection. FZD7 also was overexpressed in the 6 HCC cell lines tested and functional analysis showed that FZD7 messenger RNA (mRNA) levels correlated with enhanced cellular motility.

Results: Transfection of HCC cells with dominant-negative mutant constructs encoding a C-terminally truncated FZD7 protein decreased wild-type beta-catenin protein accumulation and reduced cell motility. More importantly, we observed beta-catenin accumulation in human HCC tumors containing the wild-type beta-catenin gene in the context of high-level FZD7 expression.

Conclusions: These observations suggest that the Wnt/beta-catenin signal transduction pathway is involved much more commonly in the molecular pathogenesis of HCC than previously recognized because FZD7 overexpression occurred early in the disease process, stabilized wild-type beta-catenin levels, and contributed to enhanced tumor cell migration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Movement
  • Cytoskeletal Proteins / analysis
  • Frizzled Receptors
  • Humans
  • Liver Neoplasms / etiology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Male
  • Middle Aged
  • Mutation
  • RNA, Messenger / analysis
  • Receptors, G-Protein-Coupled / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Trans-Activators / analysis
  • beta Catenin


  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • FZD7 protein, human
  • Frizzled Receptors
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Trans-Activators
  • beta Catenin