Original ResearchBasic and Translational—Alimentary Tractβ-Catenin and p120 Mediate PPARδ-Dependent Proliferation Induced by Helicobacter pylori in Human and Rodent Epithelia
Section snippets
Materials and Methods
Details for in vitro, ex vivo, and human studies are contained in the Supplementary data.
PPARδ Is Expressed and Is Functionally Responsive to H pylori in Gastric Epithelial Cells
To determine whether H pylori induces PPARδ expression, MKN28 gastric epithelial cells were co-cultured with a cag+ strain, 7.13, that rapidly induces gastric carcinoma in rodent models of infection.5 pparδ messenger RNA (mRNA) expression significantly increased in cells infected with H pylori, beginning at 24 hours after infection (Figure 1A), which was accompanied by increased PPARδ protein levels in whole-cell lysates, and in both the cytosol and nucleus by 48 hours after infection (Figure 1B
Discussion
Translocation of p120 to the nucleus relieves transcriptional repression that is exerted by Kaiso on β-catenin target genes possessing oncogenic properties.11 By using stable reductions of p120 in gastric epithelial cells, we identified pparδ as a p120 target that may influence carcinogenesis within the context of H pylori infection. We have previously shown that H pylori strain 7.13 induces alterations in the cellular localization of p120, which is required for regulation of mmp-7 expression,12
References (27)
- et al.
Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo
J Biol Chem
(2002) - et al.
Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation
Cell Host Microbe
(2009) - et al.
Kaiso/p120-catenin and TCF/beta-catenin complexes coordinately regulate canonical Wnt gene targets
Dev Cell
(2005) - et al.
PPARdelta activation induces COX-2 gene expression and cell proliferation in human hepatocellular carcinoma cells
Biochem Biophys Res Commun
(2003) - et al.
Effect of Helicobacter pylori eradication on gastric carcinogenesis
Lab Invest
(2008) - et al.
Helicobacter pylori suppresses glycogen synthase kinase 3beta to promote beta-catenin activity
J Biol Chem
(2008) - et al.
Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity
Cell Metab
(2008) - et al.
The role of matrix metalloproteinase-7 in redefining the gastric microenvironment in response to Helicobacter pylori
Gastroenterology
(2006) - et al.
Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation
J Steroid Biochem Mol Biol
(2003) - et al.
Helicobacter pylori: gastric cancer and beyond
Nat Rev Cancer
(2010)
Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion
Science
Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA
Science
Activation of β-catenin by carcinogenic Helicobacter pylori
Proc Natl Acad Sci U S A
Cited by (61)
A single-nucleotide polymorphism in Helicobacter pylori promotes gastric cancer development
2023, Cell Host and MicrobeHelicobacter pylori
2023, Molecular Medical Microbiology, Third EditionPPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice
2019, GastroenterologyCitation Excerpt :CXCL1 mediates neutrophil recruitment,38 and CCL20 is up-regulated in H pylori–infected gastric mucosa and attracts immune cells, such as lymphocytes and dendritic cells, toward epithelial cells.39–41 Chronic gastric inflammation, as in the cases of H pylori infection in humans and its relative H felis in mice, plays a critical role in gastric tumorigenesis.19,29 These microbial agents seem to use PPARD to promote gastritis and gastric tumorigenesis.
Loss of Tight Junction Protein Claudin 18 Promotes Progressive Neoplasia Development in Mouse Stomach
2018, GastroenterologyCitation Excerpt :High rates of cellular proliferation occur in CLDN18KM, which is similar to the mucosal response to H pylori infection. Numerous pathways are linked to the proliferative response in H pylori–mediated GC, including β-catenin,20,21 CD44,40 EFNB/EPHB receptor signaling,41,42 and HIPPO signaling.43,44 In CLDN18KM, CD44 may predominantly drive proliferation at the base of gastric glands where it is most highly expressed, whereas EFNB1/2/EPHB2 signaling may drive proliferation in the entire corpus mucosa.
Conflicts of interest The authors disclose no conflicts.