NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways

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65 Scopus citations


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 languageEnglish (US)
Pages (from-to)2756-2770
Number of pages15
JournalCell Reports
Issue number13
StatePublished - Jun 27 2017


  • 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


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