Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells
| Autor: | Claire Turbide, Kevin McGregor, Richard S. Blumberg, Uri David Akavia, Patrick T. Gunning, Celia M. T. Greenwood, Valérie Breton, Jeremy Dupaul-Chicoine, Sina Haftchenary, Sara Yumeen, Maya Saleh, Azadeh Arabzadeh, Nicole Beauchemin |
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| Rok vydání: | 2014 |
| Předmět: |
0301 basic medicine
Oncology Male Chemokine medicine.medical_specialty Colorectal cancer Article Metastasis 03 medical and health sciences Mice Carcinoembryonic antigen Antigens CD Internal medicine medicine Tumor Cells Cultured Gene silencing Animals Humans Protein Isoforms STAT3 biology Cell adhesion molecule Liver Neoplasms Gastroenterology Cell Differentiation Middle Aged medicine.disease Mice Inbred C57BL 030104 developmental biology Chemokine secretion Colonic Neoplasms biology.protein Female Colorectal Neoplasms Cell Adhesion Molecules |
| Zdroj: | Gut. 65(5) |
| ISSN: | 1468-3288 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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