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Differential effects of inactivated Axin1 and activated β-catenin mutations in human hepatocellular carcinomas

Oncogene volume 26, pages 774–780 (2007)Cite this article

Abstract

Perturbations to the Wnt signaling pathway have been implicated in a large proportion of human hepatocellular carcinomas (HCCs). Activating β-catenin mutations and loss of function mutations in Axin1 are thought to be functionally equivalent. We examined the Wnt pathway in HCC by comparing the expression of β-catenin target genes and the level of β-catenin-dependent transcriptional activation, in 45 HCC tumors and four cell lines. Among these samples, β-catenin and AXIN1 were mutated in 20 and seven cases, respectively. We found a significant correlation between activated β-catenin mutations and overexpression of mRNA for the target genes glutamine synthetase (GS), G-protein-coupled receptor (GPR)49 and glutamate transporter (GLT)-1 (P=0.0001), but not for the genes ornithine aminotransferase, LECT2, c-myc and cyclin D1. We also showed that GS is a good immunohistochemical marker of β-catenin activation in HCC. However, we observed no induction of GS, GPR49 or GLT-1 in the five inactivated Axin1 tumors. β-Catenin-dependent transcriptional activation in two Axin1-mutated HCC cell lines was much weaker than in β-catenin-mutated cell lines. Our results strongly suggest that in HCC, contrary to expectation, the loss of function of Axin1 is not equivalent to the gain of function of β-catenin. Our results also suggest that the tumor suppressor function of Axin1 in HCC may be related to another, non-Wnt pathway.

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Acknowledgements

We thank Valérie Paradis and Jacques Belghiti at Beaujon Hospital (Clichy, France) who provided four AXIN1 tumor samples for validation. We also thank all the member of the C Perret's team for their helpful discussions. This work was supported by INSERM, CNRS, the ‘Comite de Paris de la Ligue Nationale contre le Cancer’, the ‘Association pour la Recherche contre le Cancer’ and the SNFGE.

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Author notes

  1. S Benhamouche and C Godard: Equal second authors.

Authors and Affiliations

  1. INSERM U674 IFR105, Paris Saint-Louis, CEPH, Paris, France

    J Zucman-Rossi & S Boyault

  2. Département EMC, Institut Cochin, INSERM U567, CNRS UMR 8104, Université Paris5 René Descartes, Paris, France

    S Benhamouche, C Godard, G Grimber & C Perret

  3. Département d’Hepatologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France

    C Balabaud

  4. Service d’Anatomie Pathologique, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France

    C Balabaud & P Bioulac-Sage

  5. GREF Inserm E362, Université Bordeaux 2, Bordeaux, France

    A S Cunha

  6. Service de Chirurgie Digestive, Hôpital Saint-André CHU Bordeaux, Bordeaux, France

    P Bioulac-Sage

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  1. J Zucman-Rossi
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  9. C Perret
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Correspondence to C Perret.

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Zucman-Rossi, J., Benhamouche, S., Godard, C. et al. Differential effects of inactivated Axin1 and activated β-catenin mutations in human hepatocellular carcinomas. Oncogene 26, 774–780 (2007). https://doi.org/10.1038/sj.onc.1209824

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  • DOI: https://doi.org/10.1038/sj.onc.1209824

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