Cdx2 expression and intestinal metaplasia induced by H. Pylori infection of gastric cells is regulated by NOD1-Mediated innate immune responses

Naoki Asano, Akira Imatani, Tomohiro Watanabe, Yutaka Kondo, Jun Fushiya, Xiaoyi Jin, Nobuyuki Ara, Kaname Uno, Katsunori Iijima, Tomoyuki Koike, Warren Strober, Tooru Shimosegawa

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Chronic infection with the bacterial Helicobacter pylori is a major cause of gastric and duodenal ulcer disease, gastric mucosal atrophy, and cancer. H. pylori-induced expression of the intestinal epithelial-specific transcription factor caudal-related homeobox 2 (Cdx2) contributes to intestinal metaplasia, a precursor event to gastric cancer. Given a role for the bacterial pattern recognition molecule nucleotide-binding oligomerization domain 1 (NOD1) in the innate immune response to bacterial infection, we investigated mechanisms used by NOD1 to regulate H. pylori infection and its propensity towards the development of intestinal metaplasia. We found that Cdx2 was induced by H. pylori infection in both normal and neoplastic gastric epithelial cells in a manner that was inversely related to NOD1 signaling. Mechanistic investigations revealed that Cdx2 induction relied upon activation of NF-kB but was suppressed by NOD1-mediated activation of TRAF3, a negative regulator of NF-kB. In vivo, prolonged infection of NOD1-deficient mice with H. pylori led to increased Cdx2 expression and intestinal metaplasia. Furthermore, gastric epithelial cells from these mice exhibited increased nuclear expression of the NF-kB p65 subunit and decreased expression of TRAF3. Overall, our findings illuminated a role for NOD1 signaling in attenuating H. pyloriinduced Cdx2 expression in gastric epithelial cells, suggesting a rationale to augment NOD1 signaling in H. pylori-infected patients to limit their risks of accumulating precancerous gastric lesions.

Original languageEnglish
Pages (from-to)1135-1145
Number of pages11
JournalCancer Research
Volume76
Issue number5
DOIs
Publication statusPublished - 2016 Mar 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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