Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma.
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.[1]References
- Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Merle, P., de la Monte, S., Kim, M., Herrmann, M., Tanaka, S., Von Dem Bussche, A., Kew, M.C., Trepo, C., Wands, J.R. Gastroenterology (2004) [Pubmed]
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