Abstract
Although NOD2 is the major inflammatory bowel disease susceptibility gene, its role in colorectal tumorigenesis is poorly defined. Here, we show that Nod2-deficient mice are highly susceptible to experimental colorectal tumorigenesis independent of gut microbial dysbiosis. Interestingly, the expression of inflammatory genes and the activation of inflammatory pathways, including NF-κB, ERK, and STAT3 are significantly higher in Nod2−/− mouse colons during colitis and colorectal tumorigenesis, but not at homeostasis. Consistent with higher inflammation, there is greater proliferation of epithelial cells in hyperplastic regions of Nod2−/− colons. In vitro studies demonstrate that, while NOD2 activates the NF-κB and MAPK pathways in response to MDP, it inhibits TLR-mediated activation of NF-κB and MAPK. Notably, NOD2-mediated downregulation of NF-κB and MAPK is associated with the induction of IRF4. Taken together, NOD2 plays a critical role in the suppression of inflammation and tumorigenesis in the colon via downregulation of the TLR signaling pathways.
Original language | English (US) |
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Pages (from-to) | 2756-2770 |
Number of pages | 15 |
Journal | Cell Reports |
Volume | 19 |
Issue number | 13 |
DOIs | |
State | Published - Jun 27 2017 |
Keywords
- IRF4
- NF-κB
- NOD-like receptors
- NOD2
- TLR
- colitis
- colorectal tumorigenesis
- inflammation
- inflammatory bowel diseases
- negative regulation of TLR signaling
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology