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NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways
S M Nashir Udden1, Lan Peng1, Jia-Liang Gan1
1Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
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.
Insights
NOD2 deficiency increases susceptibility to colorectal cancer by promoting inflammation. NOD2 normally suppresses inflammation and tumorigenesis by downregulating TLR signaling pathways.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- NOD2 is a key susceptibility gene for inflammatory bowel disease.
- The precise role of NOD2 in colorectal cancer development remains unclear.
Purpose of the Study:
- To investigate the role of NOD2 in experimental colorectal tumorigenesis.
- To elucidate the molecular mechanisms by which NOD2 influences inflammation and epithelial cell proliferation in the colon.
Main Methods:
- Utilized Nod2-deficient (Nod2-/-) and wild-type mice in experimental colorectal cancer models.
- Analyzed inflammatory gene expression and pathway activation (NF-κB, ERK, STAT3) via qPCR and Western blotting.
- Performed in vitro studies to assess NOD2's effect on Toll-like receptor (TLR)-mediated signaling.
Main Results:
- Nod2-/- mice exhibited increased susceptibility to colorectal tumorigenesis, independent of gut microbiota changes.
- Elevated expression of inflammatory genes and activation of NF-κB, ERK, and STAT3 pathways were observed in Nod2-/- colons during colitis and tumorigenesis.
- NOD2 activation by MDP induced NF-κB and MAPK pathways, while simultaneously inhibiting TLR-mediated NF-κB and MAPK activation, a process linked to IRF4 induction.
Conclusions:
- NOD2 plays a crucial role in suppressing colon inflammation and preventing colorectal tumorigenesis.
- NOD2 exerts its protective effects by downregulating TLR signaling pathways, thereby reducing inflammation and epithelial cell proliferation.
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