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New targets of β-catenin signaling in the liver are involved in the glutamine metabolism

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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References

  • Bennoun M, Grimber G, Couton D, Seye A, Molina T, Briand P, Joulin V . 1998 Oncogene 17: 1253–1259

  • Bosch FX, Ribes J, Borras J . 1999 Semin. Liver Dis. 19: 271–285

  • Buendia MA . 2000 Semin. Cancer Biol. 10: 185–200

  • Cadoret A, Ovejero C, Saadi-Kheddouci S, Souil E, Fabre M, Romagnolo B, Kahn A, Perret C . 2001 Cancer Res. 61: 3245–3249

  • Christa L, Simon MT, Flinois JP, Gebhardt R, Brechot C, Lasserre C . 1994 Gastroenterology 106: 1312–1320

  • de La Coste A, Mignon A, Fabre M, Gilbert E, Poteu A, Van Dyke T, Kahn A, Perret C . 1999 Cancer Res. 59: 5017–5022

  • de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C . 1998 Proc. Natl. Acad. Sci. USA 95: 8847–8851

  • Ferry N, Heard JM . 1998 Hum. Gene Ther. 9: 1975–1981

  • Gebhardt R, Mecke D . 1983 EMBO J. 2: 567–570

  • Gebhardt R, Williams GM . 1995 Carcinogenesis 16: 1673–1681

  • Harada N, Miyoshi H, Murai N, Oshima H, Tamai YU, Oshima M, Taketo MM . 2002 Cancer Res. 62: 1971–1977

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW . 1998 Science 281: 1509–1512

  • Kallioniemi OP, Wagner U, Kononen J, Sauter G . 2001 Hum. Mol. Genet. 10: 657–662

  • Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T . 1999 Cancer Res. 59: 269–273

  • Kovacevic Z, McGivan JD . 1983 Physiol Rev. 63: 547–605

  • Kuo FC, Darnell Jr JE . 1991 Mol. Cell. Biol. 11: 6050–6058

  • Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, Monges G, Thomas G, Bioulac-Sage P, Zucman-Rossi J . 2001 Gastroenterology 120: 1763–1773

  • Miyasaka Y, Enomoto N, Nagayama K, Izumi N, Marumo F, Watanabe M, Sato C . 2001 Br. J. Cancer 85: 228–234

  • Osada T, Nagashima I, Tsuno NH, Kitayama J, Nagawa H . 2000 J. Hepatol. 33: 247–253

  • Palos TP, Zheng S, Howard BD . 1999 J. Neurochem. 73: 1012–1023

  • Polakis P . 2000 Genes Dev. 14: 1837–1851

  • Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y . 2000 Nat. Genet. 24: 245–250

  • Tetsu O, McCormick F . 1999 Nature 398: 422–426

  • Umeda T, Yamamoto T, Kajino K, Hino O . 2000 Int. J. Oncol. 16: 1133–1136

  • Wei Y, Fabre M, Branchereau S, Gauthier F, Perilongo G, Buendia MA . 2000 Oncogene 19: 498–504

  • Young CS, Kitamura M, Hardy S, Kitajewski J . 1998 Mol. Cell. Biol. 18: 2474–2485

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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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Correspondence to Christine Perret.

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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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