Abstract
Wnt/β-catenin signaling is frequently activated in cancer cells by stabilizing mutations of β-catenin or loss-of-function mutations of the APC tumor suppressor gene. We have analysed the role of β-catenin in the pathogenesis of hepatoblastoma (HB), an embryonic liver tumor occurring mainly in children under 2 years of age. Sequence analysis of the β-catenin NH2-terminal domain in 18 epithelial and mixed HBs revealed missense mutations in the GSK3β phosphorylation motif or interstitial deletions in 12 tumors (67%). In the remaining cases, no truncating mutation of APC could be evidenced. Immunohistochemical analysis of β-catenin in 11 HBs demonstrated nuclear/cytoplasmic accumulation of the protein in all tumors analysed, with predominant nuclear β-catenin immunostaining in undifferentiated cells. Membranous β-catenin localization was preserved only in fetal-type tumoral hepatocytes and was associated with E-cadherin expression. Moreover, we show that β-catenin is aberrantly overexpressed in a large spectrum of tumor components, including hepatocyte-like cells at various differentiation stages and heterologous elements such as squamous, osteoid and chrondroid tissues, and in occasional other mesenchymally-derived cells. These data strongly suggest that activation of β-catenin signaling is an obligatory step in HB pathogenesis, and raise the possibility that it interferes with developmental signals that specify different tissue types at early stages of hepatic differentiation.
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Acknowledgements
We are grateful to C Perret for help with β-catenin mutational analysis. We thank J Hülsken for the gift of β-catenin clone 405, H Clevers for pTOPLUC and pFOPLUC, J Zucman for providing the APC primers I and II and advice on PTT, P Paterlini for helpful discussions, and N Bâ and C-A Renard for excellent technical assistance. This work was supported in part by a grant of the Association pour la Recherche sur le Cancer (5236).
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Wei, Y., Fabre, M., Branchereau, S. et al. Activation of β-catenin in epithelial and mesenchymal hepatoblastomas. Oncogene 19, 498–504 (2000). https://doi.org/10.1038/sj.onc.1203356
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DOI: https://doi.org/10.1038/sj.onc.1203356
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