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GI cancer
Complex interplay between β-catenin signalling and Notch effectors in intestinal tumorigenesis
  1. Grégory Peignon1,2,
  2. Aurélie Durand1,2,
  3. Wulfran Cacheux1,2,
  4. Olivier Ayrault3,
  5. Benoît Terris1,2,
  6. Pierre Laurent-Puig4,
  7. Noah F Shroyer5,
  8. Isabelle Van Seuningen6,
  9. Tasuku Honjo7,
  10. Christine Perret1,2,
  11. Béatrice Romagnolo1,2
  1. 1Department of Endocrinology, Metabolism and Cancer, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
  2. 2INSERM, U1016, Paris, France
  3. 3Department of Genetics and Tumour Cell Biology, St Jude Children's Research Hospital, Memphis, Tennessee, USA
  4. 4Université Paris Descartes, Faculté de Médecine René Descartes, U775, Paris, France
  5. 5Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, College of Medicine, Ohio, USA
  6. 6INSERM, U837, Jean-Pierre Aubert Research Center, Team 5 Mucins, epithelial differentiation and carcinogenesis, Lille, France
  7. 7Department of Immunology and Genomic Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto, Japan
  1. Correspondence to Béatrice Romagnolo, Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM, U567, 24 rue du Faubourg Saint Jacques, 75014 Paris, France; beatrice.romagnolo{at}inserm.fr

Abstract

Aims The activation of β-catenin signalling is a key step in intestinal tumorigenesis. Interplay between the β-catenin and Notch pathways during tumorigenesis has been reported, but the mechanisms involved and the role of Notch remain unclear.

Methods Notch status was analysed by studying expression of the Notch effector Hes1 and Notch ligands/receptors in human colorectal cancer (CRC) and mouse models of Apc mutation. A genetic approach was used, deleting the Apc and RBP-J or Atoh1 genes in murine intestine. CRC cell lines were used to analyse the control of Hes1 and Atoh1 by β-catenin signalling.

Results Notch signalling was found to be activated downstream from β-catenin. It was rapidly induced and maintained throughout tumorigenesis. Hes1 induction was mediated by β-catenin and resulted from both the induction of the Notch ligand/receptor and Notch-independent control of the Hes1 promoter by β-catenin. Surprisingly, the strong phenotype of unrestricted proliferation and impaired differentiation induced by acute Apc deletion in the intestine was not rescued by conditional Notch inactivation. Hyperactivation of β-catenin signalling overrode the forced differention induced by Notch inhibition, through the downregulation of Atoh1, a key secretory determinant factor downstream of Notch. This process involves glycogen synthase kinase 3 β (GSK3β) and proteasome-mediated degradation. The restoration of Atoh1 expression in CRC cell lines displaying β-catenin activation was sufficient to increase goblet cell differentiation, whereas genetic ablation of Atoh1 greatly increased tumour formation in Apc mutant mice.

Conclusion Notch signalling is a downstream target of β-catenin hyperactivation in intestinal tumorigenesis. However, its inhibition had no tumour suppressor effect in the context of acute β-catenin activation probably due to the downregulation of Atoh1. This finding calls into question the use of γ-secretase inhibitors for the treatment of CRC and suggests that the restoration of Atoh1 expression in CRC should be considered as a therapeutic approach.

  • Intestine
  • β-catenin
  • RBP-J
  • Hes1
  • Atoh1
  • proliferation
  • differentiation
  • cell proliferation
  • cell signalling
  • colorectal cancer genes
  • differentiation
  • molecular carcinogenesis

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

https://doi.org/10.1136/gut.2009.204719

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    Footnotes

    • Funding This work was supported by grants from INCa, ARC, the Ligue Nationale Contre le Cancer, Inserm and the CNRS.

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval This study was conducted with the approval of the Local Ethical Commitee Paris Cochin Hospital 2002 (Paris, France).

    • Provenance and peer review Not commissioned; externally peer reviewed.