EphA2 signaling is impacted by carcinoembryonic antigen cell adhesion molecule 1-L expression in colorectal cancer liver metastasis in a cell context-dependent manner
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Azadeh Arabzadeh1, Kevin McGregor2, Valérie Breton1, Lauren Van Der Kraak1,3, Uri David Akavia1,3, Celia M.T. Greenwood2,4,5 and Nicole Beauchemin1,3,6
1Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
2Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, QC, Canada
3Department of Biochemistry, McGill University, Montreal, QC, Canada
4Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada
5Departments of Oncology and Human Genetics, McGill University, Montreal, QC, Canada
6Departments of Medicine and Oncology, McGill University, Montreal, QC, Canada
Nicole Beauchemin, email: [email protected]
Keywords: CEACAM1; CEA; CEACAM6; EPHA2; liver metastasis
Abbreviations: Carcinoembryonic antigen cell adhesion molecule 1 long isoform (CEACAM1-L or CC1-L); ephrin type-A receptor 2 (EPHA2); immunoreceptor Tyr inhibition motifs (ITIMs); glycosylphosphatidylinositol (GPI); receptor Tyr kinase (RTK)
Received: July 05, 2017 Accepted: October 05, 2017 Published: November 01, 2017
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.
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