期刊
CELL REPORTS
卷 19, 期 13, 页码 2756-2770出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.05.084
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资金
- New Investigator Award from the American Cancer Society [IRG-02-196-10]
- Harold C. Simmons Comprehensive Cancer Center (National Cancer Institute/NIH) [P30 CA142543]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RP160169]
- UT Southwestern
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-kappa 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-kappa B and MAPK pathways in response to MDP, it inhibits TLR-mediated activation of NF-kappa B and MAPK. Notably, NOD2-mediated downregulation of NF-kappa 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.
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