title: Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/beta-catenin signaling pathway in hepatocellular carcinoma cells.
abstract: 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.
authors.affiliation: 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
authors.forename: Miran
authors.initials: M
authors.lastname: Kim
authors.forename: Han Chu
authors.initials: HC
authors.lastname: Lee
authors.forename: Orkhontuya
authors.initials: O
authors.lastname: Tsedensodnom
authors.forename: Rochelle
authors.initials: R
authors.lastname: Hartley
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Lim
authors.forename: Eunsil
authors.initials: E
authors.lastname: Yu
authors.forename: Philippe
authors.initials: P
authors.lastname: Merle
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wands
mesh_terms: 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*
chemical_list: 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