Sara Najmeh
Guy Martel
Elyse MacFadden-Murphy
Raquel Farias
Paul Savage
Arielle Leone
Lucie Roussel
Jonathan Cools-Lartigue
Stephen Gowing
Julie Berube
Betty Giannias
France Bourdeau
Carlos H. F. Chan
Jonathan D. Spicer
Rebecca McClure
Morag Park
Simon Rousseau
Lorenzo E. Ferri
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
Funds: This study was funded by Canadian Institute of Health Research (Grant Number 8008959).
Received Date: 2019-09-06
Abstract
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.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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