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Intestinal tumor progression is promoted by decreased apoptosis and dysregulated Wnt signaling in Ceacam1−/− mice

Oncogene volume 27, pages 4943–4953 (2008)Cite this article

Abstract

The carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is downregulated in colonic and intestinal hyperplastic lesions as well as in other cancers, where it functions as a tumor suppressor. To investigate the functions of CEACAM1 in the normal intestine and in intestinal tumors, we generated a compound knockout mouse model and examined both Ceacam1−/− and Apc1638N/+:Ceacam1−/− mice. Ceacam1−/− intestinal cells exhibited a significant decrease in apoptosis, with no change in proliferation or migration, however. Compound Apc1638N/+:Ceacam1−/− mice demonstrated an increase in intestinal tumor multiplicity and tumor progression. Increases in intussusceptions and desmoid lesions were also observed. We have shown that CEACAM1-L associates with β-catenin by co-immunoprecipitation and colocalization in CEACAM1-L-transfected CT26 and CT51 mouse colon carcinoma cells. Ceacam1−/− enterocytes displayed decreased glycogen synthase kinase 3-β activity with corresponding nuclear localization of β-catenin. Increased T-cell factor/Lef transcriptional activity was observed in CEACAM1-null CT51 colonic cells and in Caco2 colon cancer cells in which CEACAM1 was downregulated. A significant increased expression in c-Myc and cyclin D1 targets of the Wnt signaling pathway was also revealed in the Ceacam1−/− intestine. CEACAM1 therefore actively participates in Wnt signaling in intestinal cells and its downregulation in intestinal tissue contributes to malignancy by augmenting tumor multiplicity and progression.

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Acknowledgements

We thank Dr Daniel Dufort for plasmid constructs, Dr Jason Young for antibodies and Dr Nathalie Rivard for helpful comments. This work was supported by grants from the National Cancer Institute of Canada, the Canadian Cancer Society and the Miriam and Saul Goldberg Innovative Research Award (NB) and a Canadian Institutes of Health Research Training Grant (NL).

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Authors and Affiliations

  1. McGill Cancer Centre, McGill University, Montreal, Québec, Canada

    N Leung, C Turbide & N Beauchemin

  2. Department of Biochemistry, McGill University, Montreal, Québec, Canada

    N Leung & N Beauchemin

  3. Department of Pathology, Royal Alexandra Hospital, University of Alberta, Edmonton, Alberta, Canada

    B Balachandra

  4. Department of Pathology, McGill University Health Centre, Montreal, Québec, Canada

    V Marcus

  5. Department of Medicine, McGill University, Montreal, Québec, Canada

    N Beauchemin

  6. Department of Oncology, McGill University, Montreal, Québec, Canada

    N Beauchemin

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Correspondence to N Beauchemin.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Leung, N., Turbide, C., Balachandra, B. et al. Intestinal tumor progression is promoted by decreased apoptosis and dysregulated Wnt signaling in Ceacam1−/− mice. Oncogene 27, 4943–4953 (2008). https://doi.org/10.1038/onc.2008.136

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