EphA2 signaling is impacted by carcinoembryonic antigen cell adhesion molecule 1-L expression in colorectal cancer liver metastasis in a cell context-dependent manner

  • Oncotarget. 2017 Nov 1;8(61):104330-104346. doi: 10.18632/oncotarget.22236.
Azadeh Arabzadeh  1 ,  Kevin McGregor  2 ,  Valérie Breton  1 ,  Lauren Van Der Kraak  1  3 ,  Uri David Akavia  1  3 ,  Celia M T Greenwood  2  4  5 ,  Nicole Beauchemin  1  3  6
Affiliations
  • 1. Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
  • 2. Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, QC, Canada.
  • 3. Department of Biochemistry, McGill University, Montreal, QC, Canada.
  • 4. Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
  • 5. Departments of Oncology and Human Genetics, McGill University, Montreal, QC, Canada.
  • 6. Departments of Medicine and Oncology, McGill University, Montreal, QC, Canada.
PMID: 29262644 DOI: 10.18632/oncotarget.22236
Abstract

We have shown that carcinoembryonic antigen cell adhesion molecule 1 long isoform (CEACAM1-L) expression in MC38 metastatic colorectal Cancer (CRC) cells results in liver metastasis inhibition via CCL2 and STAT3 signaling. But Other molecular mechanisms orchestrating CEACAM1-L-mediated metastasis inhibition remain to be defined. We screened a panel of mouse and human CRC cells and evaluated their metastatic outcome after CEACAM1 overexpression or downregulation. An unbiased transcript profiling and a phospho-receptor tyrosine kinase screen comparing MC38 CEACAM1-L-expressing and non-expressing (CT) CRC cells revealed reduced ephrin type-A receptor 2 (EphA2) expression and activity. An EPHA2-specific inhibitor reduced EphA2 downstream signaling in CT cells similar to that in CEACAM1-L cells with decreased proliferation and migration. Human CRC patients exhibiting high CEACAM1 in combination with low EphA2 expression benefited from longer time to first recurrence/metastasis compared to those with high EphA2 expression. With the added interaction of CEACAM6, we denoted that CEACAM1 high- and EphA2 low-expressing patient samples with lower CEACAM6 expression also exhibited a longer time to first recurrence/metastasis. In HT29 human CRC cells, down-regulation of CEACAM1 along with CEA and CEACAM6 up-regulation led to higher metastatic burden. Overall, CEACAM1-L expression in poorly differentiated CRC can inhibit liver metastasis through cell context-dependent EPHA2-mediated signaling. However, CEACAM1's role should be considered in the presence of Other CEACAM family members.

Keywords
CEA; CEACAM1; CEACAM6; EPHA2; liver metastasis.
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