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

P Merle, S de la Monte, M Kim, M Herrmann, S Tanaka… - Gastroenterology, 2004 - Elsevier
P Merle, S de la Monte, M Kim, M Herrmann, S Tanaka, A Von Dem Bussche, MC Kew…
Gastroenterology, 2004Elsevier
Background & Aims: The molecular pathogenesis of human hepatocellular carcinoma
(HCC) is understood poorly. In some tumors, activation of the Wnt/β-catenin pathway as a
result of β-catenin gene mutations has been found. However, in many other HCCs,
activation of the Wnt/β-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 …
Background & Aims
The molecular pathogenesis of human hepatocellular carcinoma (HCC) is understood poorly. In some tumors, activation of the Wnt/β-catenin pathway as a result of β-catenin gene mutations has been found. However, in many other HCCs, activation of the Wnt/β-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 β-catenin protein accumulation and reduced cell motility. More importantly, we observed β-catenin accumulation in human HCC tumors containing the wild-type β-catenin gene in the context of high-level FZD7 expression.
Conclusions
These observations suggest that the Wnt/β-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 β-catenin levels, and contributed to enhanced tumor cell migration.
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