Abstract
Inappropriate activation of the Wnt/β-catenin signaling has been implicated in the development of hepatocellular carcinoma (HCC), but exactly how β-catenin works remains to be elucidated. To identify, in vivo, the target genes of β-catenin in the liver, we have used the suppression subtractive hybridization technique and transgenic mice expressing an activated β-catenin in the liver that developed hepatomegaly. We identified three genes involved in glutamine metabolism, encoding glutamine synthetase (GS), ornithine aminotransferase (OAT) and the glutamate transporter GLT-1. By Northern blot and immunohistochemical analysis we demonstrated that these three genes were specifically induced by activation of the β-catenin pathway in the liver. In different mouse models bearing an activated β-catenin signaling in the liver known to be associated with hepatocellular proliferation we observed a marked up-regulation of these three genes. The cellular distribution of GS and GLT-1 parallels β-catenin activity. By contrast no up-regulation of these three genes was observed in the liver in which hepatocyte proliferation was induced by a signal-independent of β-catenin. In addition, the GS promoter was activated in the liver of GS+/LacZ mice by adenovirus vector-mediated β-catenin overexpression. Strikingly, the overexpression of the GS gene in human HCC samples was strongly correlated with β-catenin activation. Together, our results indicate that GS is a target of the Wnt/β-catenin pathway in the liver. Because a linkage of the glutamine pathway to hepatocarcinogenesis has already been demonstrated, we propose that regulation of these three genes of glutamine metabolism by β-catenin is a contributing factor to liver carcinogenesis.
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Acknowledgements
We are grateful to Dr F Blachier (INRA, Jouy en Josas), Dr C Desbois-Mouthon (INSERM U402, Paris) and all of the fellows of our team for helpful discussions, F Letourneur and N Lebrun for sequencing, Dr V Joulin (Institut Cochin, Paris, France) for the ASV mice and Dr J Coste (Hôpital Cochin, Paris, France) for statistical analysis. We also thank Dr Owen Parkes for editing the manuscript. This work was supported by Institut Nationale de la Santé et la Recherche Medicale, the ‘Comité de Paris de la Ligue Nationale contre le Cancer’ and the ‘Association pour la Recherche contre le Cancer’ and the ACI ‘Biologie du Développment et Physolgie Intégrative’ of the ‘Ministere de la Recherche’, France.
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Cadoret, A., Ovejero, C., Terris, B. et al. New targets of β-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene 21, 8293–8301 (2002). https://doi.org/10.1038/sj.onc.1206118
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DOI: https://doi.org/10.1038/sj.onc.1206118
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