Cdx2 Expression and Intestinal Metaplasia Induced by H. pylori Infection of Gastric Cells Is Regulated by NOD1-Mediated Innate Immune Responses

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-κB but was suppressed by NOD1-mediated activation of TRAF3, a negative regulator of NF-κB. 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-κB p65 subunit and decreased expression of TRAF3. Overall, our findings illuminated a role for NOD1 signaling in attenuating H. pylori–induced 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.

Lauren classification and individualized chemotherapy in gastric cancer

“…CDX-2 is important in the development of the intestinal mucosa and in maintaining cell morphology. CDX-2 does not appear in the normal gastric mucosa, but is expressed abnormally in intestinal metaplasia and intestinal gastric cancer ( 46 , 47 ). The expression levels of CDX-2 are markedly higher in intestinal gastric cancer compared with the diffuse type ( 46 , 47 ).…”

Genome‐wide expression profiling and bioinformatics analysis of deregulated genes in human gastric cancer tissue after gastroscopy

“…Currently, STAT3 inhibitors are emerging as a promising drug for gastric cancer . Other proteins, such as CDX2 , the S100A family and MMP3 , are known to be important regulators of human gastric cancer metastasis and prognosis …”

miR-17-92 functions as an oncogene and modulates NF-κB signaling by targeting TRAF3 in MGC-803 human gastric cancer cells

“…TRAF3 functions as an upstream regulator of NF-κB signaling, and suppresses NF-κB activity by constantly mediating the degradation of NF-κB-inducing kinase (NIK) (50). The downregulation of TRAF3 in NOD1 ligand-stimulated cells leads to enhanced NF-κB reporter activity, while it increases TRAF3 expression and suppresses NF-κB activity (51). In this study, we found that both the canonical and non-canonical NF-κB activities were activated in the MGC-803 gastric cancer cells due to the introduction of the miR-17-92 cluster.…”