Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/beta-catenin signaling pathway in hepatocellular carcinoma cells.
OBJECTIVE
The canonical Wnt signaling is frequently activated in human hepatocellular carcinoma (HCC). We previously demonstrated that upregulation of Frizzled-7 receptor (FZD7) in HCC was associated with nuclear accumulation of wild-type beta-catenin. Here, we investigated Wnt ligand(s) that may activate the Wnt/beta-catenin pathway through FZD7 in HCC cells.


METHODS
To identify Wnt ligand expression, RT-PCR was performed in HCC cells. To evaluate the function of Wnt3 and FZD7 in HCC, we utilized Wnt3 overexpressing FOCUS HCC cells (FOCUS-Wnt3) and human tumors.


RESULTS
In hepatitis B virus (HBV)-induced HCC, Wnt3 was upregulated in tumor and peritumoral tissues compared to normal liver and downstream beta-catenin target genes were also increased in these samples. Activation of the Wnt/beta-catenin pathway in FOCUS-Wnt3 cells was demonstrated by beta-catenin accumulation, enhanced TCF transcriptional activity and proliferation rate. The activation of Wnt/beta-catenin signaling in FOCUS-Wnt3 was abolished by a knockdown of FZD7 expression by siRNA. More important, a specific Wnt3-FZD7 interaction was observed by co-immunoprecipitation experiments, which suggest that the action of Wnt3 was mediated via FZD7.


CONCLUSIONS
These findings demonstrate a functional interaction between Wnt3 and FZD7 leading to activation of the Wnt/beta-catenin signaling pathway in HCC cells and may play a role during hepatocarcinogenesis.
Kim
Miran
M
Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, 55 Claverick Street, Providence, RI 02903, USA. Miran_Kim@brown.edu
Lee
Han Chu
HC
Tsedensodnom
Orkhontuya
O
Hartley
Rochelle
R
Lim
Young-Suk
YS
Yu
Eunsil
E
Merle
Philippe
P
Wands
Jack R
JR
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051157:Frizzled Receptors / Q000502:physiology*; D006509:Hepatitis B / Q000150:complications; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D060508:Wnt3 Protein; D051176:beta Catenin / Q000502:physiology*
C115810:FZD7 protein, human; D051157:Frizzled Receptors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C555507:WNT3 protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin