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Gastroenterology. 2004 Oct;127(4):1110-22.

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

Author information

1
The Liver Research Center, Department of Medicine and Pathology, Brown Medical School, Providence, Rhode Island 02903, USA.

Abstract

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.

PMID:
15480989
DOI:
10.1053/j.gastro.2004.07.009
[Indexed for MEDLINE]

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