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Activation of β-catenin in epithelial and mesenchymal hepatoblastomas

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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References

  • Aberle H, Bauer A, Stappert J, Kispert A and Kemler R. . 1997 EMBO J. 16: 3797–3804.

  • Aberle H, Schwartz H and Kemler R. . 1996 J. Cell. Biochem. 61: 514–523.

  • Blaker H, Hofmann WJ, Rieker RJ, Penzel R, Graf M and Otto HF. . 1999 Genes Chromosomes Cancer 25: 399–402.

  • Cadigan KM and Nusse R. . 1997 Genes Dev. 11: 3286–3305.

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

  • Desdouets C, Fabre M, Gauthier F, Bréchot C and Sobczak-Thépot J. . 1995 J. Hepatol. 23: 569–577.

  • Garcia-Rostan G, Tallini G, Herrero A, D’Aquila TG, Carcangiu ML and Rimm DL. . 1999 Cancer Res. 59: 1811–1815.

  • Giardiello FM, Petersen GM, Brensinger JD, Luce MC, Cayouette MC, Bacon J, Booker SV and Hamilton SR. . 1996 Gut 39: 867–869.

  • Hülsken J, Birchmeier W and Behrens J. . 1994 J. Cell Biol. 127: 2061–2069.

  • Iwao K, Nakamori S, Kameyama M, Imaoka S, Kinoshita M, Fukui T, Ishiguro S, Nakamura Y and Miyoshi Y. . 1998 Cancer Res. 58: 1021–1026.

  • Kinzler K and Vogelstein B. . 1996 Cell 87: 159–170.

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

  • Koesters R, Ridder R, Kopp-Schneider A, Betts D, Adams V, Niggli F, Briner J and von Knebel Doeberitz M. . 1999 Cancer Res. 59: 3880–3882.

  • Kolligs FT, Hu G, Dang CV and Fearon ER. . 1999 Mol. Cell. Biol. 19: 5696–5706.

  • Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B and Clevers H. . 1997 Science 275: 1784–1787.

  • Kurahashi H, Takami K, Oue T, Kusafuka T, Okada A, Tawa A, Okada S and Nishisho I. . 1995 Cancer Res. 55: 5007–5011.

  • Legoix P, Bluteau O, Bayer J, Perret C, Balabaud C, Belghiti J, Franco D, Thomas G, Laurent-Puig P and Zucman-Rossi J. . 1999 Oncogene 18: 4044–4046.

  • Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T and Nakamura Y. . 1998 Cancer Res. 58: 2524–2527.

  • Oda H, Imai Y, Nakatsuru Y, Hata J and Ishikawa T. . 1996 Cancer Res. 56: 3320–3323.

  • Olschwang S, Hamelin R, Laurent-Puig P, Thuille B, de Rycke Y, Li Y-J, Muzeau F, Girodet J, Salmon RJ and Thomas G. . 1997 Proc. Natl. Acad. Sci. USA 94: 12122–12127.

  • Orford K, Orford CC and Byers SW. . 1999 J. Cell Biol. 146: 855–868.

  • Polakis P. . 1999 Curr. Opin. Genet. Dev. 9: 15–21.

  • Powell SM, Petersen GM, Krush AJ, Booker S, Jen J, Giardiello FM, Hamilton SR, Vogelstein B and Kinzler KW. . 1993 New Eng. J. Med. 329: 1982–1987.

  • Sadot E, Simcha I, Shtutman M, Ben-Ze’ev A and Geiger B. . 1998 Proc. Natl. Acad. Sci. USA 95: 15339–15344.

  • Siegfried E, Wilder EL and Perrimon N. . 1994 Nature 367: 76–80.

  • Sparks AB, Morin PJ, Vogelstein B and Zinsler KW. . 1998 Cancer Res. 58: 1130–1134.

  • Stocker JT and Conran RM. . 1997 In: Liver Cancer. Churchill Livingstone: New York.

    Google Scholar 

  • Tran van Nhieu J, Renard CA, Wei Y, Cherqui D, Zafrani ES and Buendia MA. . 1999 Am. J. Pathol. 155: 703–710.

  • Voeller HJ, Truica CI and Gelmann EP. . 1998 Cancer Res. 58: 2520–2523.

  • Wei Y and Ganem D. . 1998 J. Virol. 72: 2089–2096.

  • Weinberg AG and Finegold MJ. . 1983 Hum. Pathol. 14: 512–537.

  • Yost C, Torres M, Miller JR, Huang E, Kimelman D and Moon RT. . 1996 Genes Dev. 10: 1443–1454.

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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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