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NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways.


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-?B, 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-?B and MAPK pathways in response to MDP, it inhibits TLR-mediated activation of NF-?B and MAPK. Notably, NOD2-mediated downregulation of NF-?B 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.

SUBMITTER: Udden SMN 

PROVIDER: S-EPMC6032983 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways.

Udden S M Nashir SMN   Peng Lan L   Gan Jia-Liang JL   Shelton John M JM   Malter James S JS   Hooper Lora V LV   Zaki Md Hasan MH  

Cell reports 20170601 13


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<sup>-/-</sup> mouse colons during colitis and colorectal tumorig  ...[more]

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