NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways

S. M.Nashir Udden, Lan Peng, Jia Liang Gan, John M. Shelton, James S. Malter, Lora V. Hooper, Md Hasan Zaki

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2756-2770
Number of pages15
JournalCell Reports
Volume19
Issue number13
DOIs
StatePublished - Jun 27 2017

Fingerprint

Carcinogenesis
Down-Regulation
Genes
Chemical activation
Colon
Dysbiosis
Inflammation
Disease Susceptibility
Colitis
Inflammatory Bowel Diseases
Transcriptional Activation
Homeostasis
Epithelial Cells

Keywords

  • colitis
  • colorectal tumorigenesis
  • inflammation
  • inflammatory bowel diseases
  • IRF4
  • negative regulation of TLR signaling
  • NF-κB
  • NOD-like receptors
  • NOD2
  • TLR

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways. / Udden, S. M.Nashir; Peng, Lan; Gan, Jia Liang; Shelton, John M.; Malter, James S.; Hooper, Lora V.; Zaki, Md Hasan.

In: Cell Reports, Vol. 19, No. 13, 27.06.2017, p. 2756-2770.

Research output: Contribution to journalArticle

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