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Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells
  1. Azadeh Arabzadeh1,
  2. Jeremy Dupaul-Chicoine2,
  3. Valérie Breton1,
  4. Sina Haftchenary3,
  5. Sara Yumeen1,
  6. Claire Turbide1,
  7. Maya Saleh4,
  8. Kevin McGregor5,
  9. Celia M T Greenwood5,
  10. Uri David Akavia2,
  11. Richard S Blumberg6,
  12. Patrick T Gunning3,
  13. Nicole Beauchemin1
  1. 1Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
  2. 2Department of Biochemistry, McGill University, Montreal, Quebec, Canada
  3. 3Department of Chemistry, University of Toronto, Toronto, Ontario, Canada
  4. 4Complex Trait Group, McGill University, Montreal, Quebec, Canada
  5. 5Departments of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada
  6. 6Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Nicole Beauchemin, Goodman Cancer Research Centre, McIntyre Building, McGill University, Room 702A, 3655 Promenade Sir-William-Osler, Montreal, Quebec, Canada H3G 1Y6; nicole.beauchemin@mcgill.ca

Abstract

Objective Nearly 20%–29% of patients with colorectal cancer (CRC) succumb to liver or lung metastasis and there is a dire need for novel targets to improve the survival of patients with metastasis. The long isoform of the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1-L or CC1-L) is a key regulator of immune surveillance in primary CRC, but its role in metastasis remains largely unexplored. We have examined how CC1-L expression impacts on colon cancer liver metastasis.

Design Murine MC38 transfected with CC1-L were evaluated in vitro for proliferation, migration and invasion, and for in vivo experimental liver metastasis. Using shRNA silencing or pharmacological inhibition, we delineated the role in liver metastasis of Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) downstream of CC1-L. We further assessed the clinical relevance of these findings in a cohort of patients with CRC.

Results MC38-CC1-L-expressing cells exhibited significantly reduced in vivo liver metastasis and displayed decreased CCL2 chemokine secretion and reduced STAT3 activity. Down-modulation of CCL2 expression and pharmacological inhibition of STAT3 activity in MC38 cells led to reduced cell invasion capacity and decreased liver metastasis. The clinical relevance of our findings is illustrated by the fact that high CC1 expression in patients with CRC combined with some inflammation-regulated and STAT3-regulated genes correlate with improved 10-year survival.

Conclusions CC1-L regulates inflammation and STAT3 signalling and contributes to the maintenance of a less-invasive CRC metastatic phenotype of poorly differentiated carcinomas.

  • CELL ADHESION MOLECULES
  • CHEMOKINES
  • COLORECTAL CANCER
  • COLORECTAL METASTASES
  • INFLAMMATION

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