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

N Leung1, C Turbide, B Balachandra

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

Oncogene
|May 6, 2008
PubMed

Insights

Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) loss reduces apoptosis, promoting intestinal tumor growth. CEACAM1 deficiency activates Wnt signaling, increasing tumor multiplicity and progression in mice.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gastroenterology

Background:

  • Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) acts as a tumor suppressor, often downregulated in cancers.
  • Its role in normal intestinal function and tumorigenesis requires further elucidation.

Purpose of the Study:

  • To investigate the function of CEACAM1 in the normal intestine and in intestinal tumors.
  • To determine the impact of CEACAM1 deficiency on intestinal cell apoptosis, proliferation, and migration.
  • To analyze the effect of CEACAM1 loss on Wnt signaling pathways and tumor development.

Main Methods:

  • Generation of compound knockout mouse models (Ceacam1(-/-) and Apc(1638N/+):Ceacam1(-/-)).
  • Assessment of intestinal cell apoptosis, proliferation, and migration.
  • Co-immunoprecipitation and colocalization studies to examine CEACAM1-beta-catenin interactions.
  • Analysis of Wnt signaling pathway activity (GSK3-beta, beta-catenin, TCF/LEF, c-Myc, cyclin D1).

Main Results:

  • Ceacam1(-/-) intestinal cells showed decreased apoptosis but no changes in proliferation or migration.
  • Apc(1638N/+):Ceacam1(-/-) mice exhibited increased intestinal tumor multiplicity and progression.
  • CEACAM1-L was found to associate with beta-catenin.
  • CEACAM1 deficiency led to decreased GSK3-beta activity, nuclear beta-catenin localization, and enhanced Wnt/TCF/LEF transcriptional activity.
  • Upregulation of c-Myc and cyclin D1 was observed in Ceacam1(-/-) intestine.

Conclusions:

  • CEACAM1 actively participates in Wnt signaling regulation within intestinal cells.
  • Downregulation of CEACAM1 in intestinal tissue contributes to malignancy by increasing tumor multiplicity and progression.
  • CEACAM1 loss promotes intestinal tumorigenesis through modulation of apoptosis and Wnt pathway activation.

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