Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma.
OBJECTIVE
The molecular mechanisms of hepatocarcinogenesis remain largely unknown. Previous studies suggest that activation of the Wnt/beta-catenin pathway is important during hepatocyte transformation but the role of Frizzled receptor (FZD) in this process has not been defined. Here we investigate activation of this pathway by FZD using transgenic hepatocellular carcinoma (HCC) murine models.


METHODS
We employed single (c-myc, SV40-Tag) and established double [insulin receptor substrate-1 (IRS-1/c-myc) and hepatitis Bx protein (X/c-myc)] transgenic lines and all developed HCC. Expression of 9 FZD was measured by real time RT-PCR and Western blot analysis. Phosphorylation and cellular accumulation of beta-catenin were assessed in both dysplastic tissue and tumors. We investigated the effect of a dominant negative (DN) FZD7 on TCF transcriptional activity in a SV40 derived HCC cell line.


RESULTS
FZD7 was highly overexpressed at the mRNA and protein level(s) in HCC and occurred in dysplasia. Upregulation of FZD7 was associated with reduced phosphorylation of beta-catenin and led to nuclear accumulation in HCC tumors. Ectopic expression of a DN FZD7 construct decreased TCF transcriptional activity in tumor cells.


CONCLUSIONS
These observations suggest that upregulation of FZD7 receptors in association with activation of the canonical Wnt/beta-catenin pathway is a common molecular event in HCC.
Merle
Philippe
P
Department of Medicine and Pathology, Brown Medical School, The Liver Research Center, Providence, 55 Claverick St., 4th Floor, Providence, RI 02903, Rhode Island 02903, USA.
Kim
Miran
M
Herrmann
Marc
M
Gupte
Anand
A
Lefrançois
Lydie
L
Califano
Sophia
S
Trépo
Christian
C
Tanaka
Shinji
S
Vitvitski
Ludmila
L
de la Monte
Suzanne
S
Wands
Jack R
JR
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002458:Cell Fractionation; D051157:Frizzled Receptors; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009857:Oncogenes; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D051157:Frizzled Receptors; C492041:Fzd7 protein, mouse; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D051176:beta Catenin