title: Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells.
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.
  
  
  METHODS
  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.
authors: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors: Azadeh
authors: A
authors: Arabzadeh
authors: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors: Jeremy
authors: J
authors: Dupaul-Chicoine
authors: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors: Valérie
authors: V
authors: Breton
authors: Department of Chemistry, University of Toronto, Toronto, Ontario, Canada.
authors: Sina
authors: S
authors: Haftchenary
authors: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors: Sara
authors: S
authors: Yumeen
authors: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors: Claire
authors: C
authors: Turbide
authors: Complex Trait Group, McGill University, Montreal, Quebec, Canada.
authors: Maya
authors: M
authors: Saleh
authors: Departments of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.
authors: Kevin
authors: K
authors: McGregor
authors: Departments of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.
authors: Celia M T
authors: CM
authors: Greenwood
authors: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors: Uri David
authors: UD
authors: Akavia
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Richard S
authors: RS
authors: Blumberg
authors: Department of Chemistry, University of Toronto, Toronto, Ontario, Canada.
authors: Patrick T
authors: PT
authors: Gunning
authors: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors: Nicole
authors: N
authors: Beauchemin
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000473:pathology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020033:Protein Isoforms / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D020033:Protein Isoforms
keywords: CELL ADHESION MOLECULES; CHEMOKINES; COLORECTAL CANCER; COLORECTAL METASTASES; INFLAMMATION