Dataset Information

CMTM3 protects the gastric epithelial cells from apoptosis and promotes IL-8 by stabilizing NEMO during Helicobacter pylori infection.

ABSTRACT:

Background

CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) plays an important role in cancer development. Although Helicobacter pylori (H. pylori) infection is a main cause of gastric cancer, the function of CMTM3 during H. pylori infection remains unclear. CMTM3 expression levels in tissues from H. pylori-infected patients and cells co-cultured with H. pylori were analyzed. qRT-PCR and ELISA were used to investigate the effects of CMTM3 on interleukin 8 (IL-8) expression. Annexin V/propidium iodide staining was performed to evaluate the function of CMTM3 in the apoptosis of gastric epithelial cells. Proteomic analysis was performed to explore the underlying mechanism of CMTM3 during H. pylori infection. The interaction between CMTM3 and NEMO was determined via co-immunoprecipitation, HA-ubiquitin pull-down assay, and immunofluorescence.

Results

H. pylori induced a significant increase in CMTM3 expression. CMTM3 inhibited gastric mucosal epithelial cells from apoptosis and increased the expression level of IL-8 during H. pylori infection. KEGG pathway enrichment analysis revealed that differentially expressed proteins were involved in epithelial cell signaling in H. pylori infection. CMTM3 directly interacted with NEMO, which promoted protein stabilization by down-regulation of its ubiquitylation.

Conclusions

CMTM3 reduces apoptosis and promotes IL-8 expression in the gastric epithelial cells by stabilizing NEMO during H. pylori infection. These findings characterize a new role for CMTM3 in host-pathogen interactions and provide novel insight into the molecular regulation of NEMO.

SUBMITTER: Zhang J

PROVIDER: S-EPMC9924195 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

CMTM3 protects the gastric epithelial cells from apoptosis and promotes IL-8 by stabilizing NEMO during Helicobacter pylori infection.

Zhang Jing J Ning Jing J Fu Weiwei W Shi Yanyan Y Zhang Jing J Ding Shigang S

Gut pathogens 20230213 1

<h4>Background</h4>CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) plays an important role in cancer development. Although Helicobacter pylori (H. pylori) infection is a main cause of gastric cancer, the function of CMTM3 during H. pylori infection remains unclear. CMTM3 expression levels in tissues from H. pylori-infected patients and cells co-cultured with H. pylori were analyzed. qRT-PCR and ELISA were used to investigate the effects of CMTM3 on interleukin 8 (IL-8) expression. Ann ...[more]

PMID: 36782312

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Project description:BACKGROUND & AIMS:Helicobacter pylori infection disrupts the balance between gastric epithelial cell proliferation and apoptosis, which is likely to lower the threshold for the development of gastric adenocarcinoma. H pylori infection is associated with epidermal growth factor (EGF) receptor (EGFR) activation through metalloproteinase-dependent release of EGFR ligands in gastric epithelial cells. Because EGFR signaling regulates cell survival, we investigated whether activation of EGFR following H pylori infection promotes gastric epithelial survival. METHODS:Mouse conditionally immortalized stomach epithelial cells (ImSt) and a human gastric epithelial cell line, AGS cells, as well as wild-type and kinase-defective EGFR (EGFRwa2) mice, were infected with the H pylori cag+ strain 7.13. Apoptosis, caspase activity, EGFR activation (phosphorylation), and EGFR downstream targets were analyzed. RESULTS:Inhibiting EGFR kinase activity or decreasing EGFR expression significantly increased H pylori-induced apoptosis in ImSt. Blocking H pylori-induced EGFR activation with a heparin-binding (HB)-EGF neutralizing antibody or abrogating a disintegrin and matrix metalloproteinase-17 (ADAM-17) expression increased apoptosis of H pylori-infected AGS and ImSt, respectively. Conversely, pretreatment of ImSt with HB-EGF completely blocked H pylori-induced apoptosis. H pylori infection stimulated gastric epithelial cell apoptosis in EGFRwa2 but not in wild-type mice. Furthermore, H pylori-induced EGFR phosphorylation stimulated phosphotidylinositol-3'-kinase-dependent activation of the antiapoptotic factor Akt, increased expression of the antiapoptotic factor Bcl-2, and decreased expression of the proapoptotic factor Bax. CONCLUSIONS:EGFR activation by H pylori infection has an antiapoptotic effect in gastric epithelial cells that appears to involve Akt signaling and Bcl family members. These findings provide important insights into the mechanisms of H pylori-associated tumorigenesis.

Project description:Helicobacter pylori infection is the predominant risk factor for the development of gastric cancer. Risk is enhanced by specific H. pylori virulence factors, diet, and the inflammatory response. Chronic activation of T helper (Th) 1 and Th17 pathways contributes to prolonged inflammation; yet, higher expression of IL-17 receptor (IL-17RA) is a favorable prognostic marker for survival after gastric cancer diagnosis. The protective impact of IL-17RA signaling is not understood. To investigate if IL-17RA signaling protects during H. pylori-induced carcinogenesis, the transgenic InsGAStg/tg mouse, which is prone to H. pylori-induced gastric cancer, was utilized. InsGAStg/tg mice and InsGAStg/tgIl17ra-/- mice were infected with a cag type 4 secretion system (T4SS) positive H. pylori strain for up to 6 months. Six weeks post-infection, IL-17RA deficiency led to increased bacterial burden, increased gastritis, and development of lymphoid follicles. Increased inflammation was associated with heightened cellular proliferation and earlier loss of parietal and chief cells in InsGAStg/tgIl17ra-/- mice. Gastric cancers developed more frequently by 3- and 6-months post-infection in H. pylori-infected InsGAStg/tgIl17ra-/- mice compared to InsGAStg/tg mice. Chronic inflammation was exacerbated with IL-17RA deficiency, characterized by elevated Th1/Th17 cytokines, increased B cell infiltration, and enhanced IgA production, despite reduced expression of the polymeric immunoglobulin receptor. Further, paragastric lymph nodes of InsGAStg/tgIl17ra-/- mice were enlarged relative to controls and displayed altered gene expression profiles. Increased inflammation was accompanied by a significant increase in Cybb expression, which encodes NADPH oxidase 2, suggesting that increased oxidative damage may occur in the absence of IL-17RA. Further, there is increased phosphorylation of histone 2AX in IL-17RA deficient mice, indicating that the DNA damage response is highly activated. These data suggest that IL-17RA signaling activates a protective pathway to prevent excessive inflammation which otherwise can lead to increased oxidative stress, DNA damage, and drive gastric carcinogenesis after H. pylori infection.

Dataset Information

CMTM3 protects the gastric epithelial cells from apoptosis and promotes IL-8 by stabilizing NEMO during Helicobacter pylori infection.

Background

Results

Conclusions

Publications

CMTM3 protects the gastric epithelial cells from apoptosis and promotes IL-8 by stabilizing NEMO during Helicobacter pylori infection.

Similar Datasets

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