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Activation of the pattern recognition receptor NOD1 augments colon cancer metastasis |
Henry Y. Jiang1,2, Sara Najmeh1,2, Guy Martel3, Elyse MacFadden-Murphy3, Raquel Farias3, Paul Savage4, Arielle Leone1,2, Lucie Roussel3, Jonathan Cools-Lartigue1,2, Stephen Gowing1,2, Julie Berube3, Betty Giannias1, France Bourdeau1, Carlos H. F. Chan5, Jonathan D. Spicer1,2, Rebecca McClure6, Morag Park4, Simon Rousseau3, Lorenzo E. Ferri1,2( ) |
1. Thoracic and Upper GI Cancer Research Laboratories, Research Institute of McGill University Health Centre, 1001 Decarie Boulevard, Block E, Lab #E02-4134, Montreal, QC H4A 3J1, Canada 2. Department of Experimental Surgery and Department of Surgery, McGill University, 1650 Cedar Avenue, Montreal, QC H3G 1A4, Canada 3. Meakins-Christie Laboratories, Research Institute of McGill University Health Centre, 1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada 4. The Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, Montreal, QC H3A 1A3, Canada 5. Department of Surgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA 6. Department of Pathology, Health Sciences North, 41 Ramsey Lake Road, Sudbury, ON, Canada |
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Abstract While emerging data suggest nucleotide oligomerization domain receptor 1 (NOD1), a cytoplasmic pattern recognition receptor, may play an important and complementary role in the immune response to bacterial infection, its role in cancer metastasis is entirely unknown. Hence, we sought to determine the effects of NOD1 on metastasis. NOD1 expression in paired human primary colon cancer, human and murine colon cancer cells were determined using immunohistochemistry and immunoblotting (WB). Clinical significance of NOD1 was assessed using TCGA survival data. A series of in vitro and in vivo functional assays, including adhesion, migration, and metastasis, was conducted to assess the effect of NOD1. C12-iE-DAP, a highly selective NOD1 ligand derived from gram-negative bacteria, was used to activate NOD1. ML130, a specific NOD1 inhibitor, was used to block C12-iE-DAP stimulation. Stable knockdown (KD) of NOD1 in human colon cancer cells (HT29) was constructed with shRNA lentiviral transduction and the functional assays were thus repeated. Lastly, the predominant signaling pathway of NOD1-activation was identified using WB and functional assays in the presence of specific kinase inhibitors. Our data demonstrate that NOD1 is highly expressed in human colorectal cancer (CRC) and human and murine CRC cell lines. Clinically, we demonstrate that this increased NOD1 expression negatively impacts survival in patients with CRC. Subsequently, we identify NOD1 activation by C12-iE-DAP augments CRC cell adhesion, migration and metastasis. These effects are predominantly mediated via the p38 mitogen activated protein kinase (MAPK) pathway. This is the first study implicating NOD1 in cancer metastasis, and thus identifying this receptor as a putative therapeutic target.
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Keywords
NOD1
iE-DAP
ML130
colon cancer
metastasis
cancer-extracellular matrix adhesion
cancer migration
p38 MAPK activation
intravital microscopy
survival analysis
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Corresponding Author(s):
Lorenzo E. Ferri
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Issue Date: 23 March 2020
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