HGF/c-Met related activation of β-catenin in hepatoblastoma
1 Children's Cancer Research Group, University of Otago, Christchurch, Christchurch, New Zealand
2 Children's Cancer and Leukaemia Group, University of Leicester, Leicester LE1 6TH (UK
3 SIAK Co-ordinating Center, Effingerstrasse 40, Bern, Switzerland
4 Department of Pathology, Canterbury Health Laboratories, Christchurch 8140, New Zealand
5 Institute of Pathology, University of Bern, Murtenstrasse 31, H-3010, Bern, Switzerland
Journal of Experimental & Clinical Cancer Research 2011, 30:96 doi:10.1186/1756-9966-30-96Published: 12 October 2011
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.
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.
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.
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.