HGF-c-Met related activation of β-catenin in hepatoblastomaReportar como inadecuado




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Journal of Experimental and Clinical Cancer Research

, 30:96

First Online: 12 October 2011Received: 28 June 2011Accepted: 12 October 2011

Abstract

BackgroundActivation 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.

MethodsWe 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.

ResultsAberrant 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.

ResultsWe 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.

Electronic supplementary materialThe online version of this article doi:10.1186-1756-9966-30-96 contains supplementary material, which is available to authorized users.

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Autor: Rachel Purcell - Margaret Childs - Rudolf Maibach - Carina Miles - Clinton Turner - Arthur Zimmermann - Michael Sullivan

Fuente: https://link.springer.com/



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