Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma.
OBJECTIVE
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.
The Liver Research Center, Department of Medicine and Pathology, Brown Medical School, Providence, Rhode Island 02903, USA.
Philippe
P
Merle
Suzanne
S
de la Monte
Miran
M
Kim
Marc
M
Herrmann
Shinji
S
Tanaka
Annette
A
Von Dem Bussche
Michael C
MC
Kew
Christian
C
Trepo
Jack R
JR
Wands
D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000032:analysis; D051157:Frizzled Receptors; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012333:RNA, Messenger / Q000032:analysis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000032:analysis; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C115810:FZD7 protein, human; D051157:Frizzled Receptors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D051176:beta Catenin