HGF/c-Met related activation of -catenin in hepatoblastoma

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. © 2011 purcell et al; licensee biomed central ltd.