title: HGF/c-Met related activation of β-catenin in hepatoblastoma.
abstract: BACKGROUND
  Activation of beta-catenin is a hallmark of hepatoblastoma (HB) and appears to play a crucial role in its pathogenesis. While aberrant accumulation of the beta-catenin is a common event in HB, mutations or deletions in CTNNB1 (beta-catenin gene) do not always account for the high frequency of protein expression. In this study we have investigated alternative activation of beta-catenin by HGF/c-Met signaling in a large cohort of 98 HB patients enrolled in the SIOPEL-3 clinical trial.
  
  
  METHODS
  We performed immunohistochemistry, using antibodies to total beta-catenin and tyrosine654-phosphorylated beta-catenin, which is a good surrogate marker of HGF/c-Met activation. CTNNB1 mutation analysis was also carried out on all samples. We also investigated beta-catenin pathway activation in two liver cancer cell lines, HuH-6 and HuH-7.
  
  
  RESULTS
  Aberrant beta-catenin expression was seen in the cytoplasm and/or nucleus of 87% of tumour samples. Our results also revealed a large subset of HB, 83%, with cytoplasmic expression of tyrosine654-phosphorylated beta-catenin and 30% showing additional nuclear accumulation. Sequence analysis revealed mutations in 15% of our cohort. Statistical analysis showed an association between nuclear expression of c-Met-activated beta-catenin and wild type CTNNB1 (P-value = 0.015). Analysis of total beta-catenin and Y654-beta-catenin in response to HGF activation in the cell lines, mirrors that observed in our HB tumour cohort.
  
  
  RESULTS
  We identified a significant subset of hepatoblastoma patients for whom targeting of the c-Met pathway may be a treatment option and also demonstrate distinct mechanisms of beta-catenin activation in HB.
authors: Children's Cancer Research Group, University of Otago, Christchurch, Christchurch, New Zealand. rachel.purcell@otago.ac.nz
authors: Rachel
authors: R
authors: Purcell
authors: Margaret
authors: M
authors: Childs
authors: Rudolf
authors: R
authors: Maibach
authors: Carina
authors: C
authors: Miles
authors: Clinton
authors: C
authors: Turner
authors: Arthur
authors: A
authors: Zimmermann
authors: Michael
authors: M
authors: Sullivan
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002467:Cell Nucleus / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D015331:Cohort Studies; D003593:Cytoplasm / Q000378:metabolism; D004273:DNA, Neoplasm; D004317:Doxorubicin / Q000008:administration & dosage; D005500:Follow-Up Studies; D018197:Hepatoblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007390:International Agencies; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011446:Prospective Studies; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051176:beta Catenin; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D004317:Doxorubicin; D016190:Carboplatin; D019859:Proto-Oncogene Proteins c-met; D002945:Cisplatin