β-Catenin and p120 mediate PPARδ-dependent proliferation induced by Helicobacter pylori in human and rodent epithelia.

Nagy TA, Wroblewski LE, Wang D, Piazuelo MB, Delgado A, Romero-Gallo J, Noto J, Israel DA, Ogden SR, Correa P, Cover TL, Peek RM
Gastroenterology. 2011 141 (2): 553-64

PMID: 21704622 · PMCID: PMC3152603 · DOI:10.1053/j.gastro.2011.05.004

BACKGROUND & AIMS - Colonization of gastric mucosa by Helicobacter pylori leads to epithelial hyperproliferation, which increases the risk for gastric adenocarcinoma. One H pylori virulence locus associated with cancer risk, cag, encodes a secretion system that transports effectors into host cells and leads to aberrant activation of β-catenin and p120-catenin (p120). Peroxisome proliferator-activated receptor (PPAR)δ is a ligand-activated transcription factor that affects oncogenesis in conjunction with β-catenin. We used a carcinogenic H pylori strain to define the role of microbial virulence constituents and PPARδ in regulating epithelial responses that mediate development of adenocarcinoma.

METHODS - Gastric epithelial cells or colonies were co-cultured with the H pylori cag(+) strain 7.13 or cagE(-), cagA(-), soluble lytic transglycosylase(-), or cagA(-)/soluble lytic transglycosylase(-) mutants. Levels of PPARδ and cyclin E1 were determined by real-time, reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy; proliferation was measured in 3-dimensional culture. PPARδ and Ki67 expression were determined by immunohistochemical analysis of human biopsies and rodent gastric mucosa.

RESULTS - H pylori induced β-catenin- and p120-dependent expression and activation of PPARδ in gastric epithelial cells, which were mediated by the cag secretion system substrates CagA and peptidoglycan. H pylori stimulated proliferation in vitro, which required PPARδ-mediated activation of cyclin E1; H pylori did not induce expression of cyclin E1 in a genetic model of PPARδ deficiency. PPARδ expression and proliferation in rodent and human gastric tissue was selectively induced by cag(+) strains and PPARδ levels normalized after eradication of H pylori.

CONCLUSIONS - The H pylori cag secretion system activates β-catenin, p120, and PPARδ, which promote gastric epithelial cell proliferation via activation of cyclin E1. PPARδ might contribute to gastric adenocarcinoma development in humans.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

MeSH Terms (21)

Adenocarcinoma Animals Antigens, Bacterial Bacterial Proteins beta Catenin Catenins Cell Proliferation Cells, Cultured Cell Transformation, Neoplastic Cyclin E Epithelial Cells Gastric Mucosa Gerbillinae Helicobacter Infections Helicobacter pylori Humans Ki-67 Antigen Oncogene Proteins PPAR delta Signal Transduction Stomach Neoplasms

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