β-Catenin and p120 Mediate PPARδ-Dependent Proliferation Induced by Helicobacter pylori in Human and Rodent Epithelia

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 beta-catenin and p120-catenin (p120). Peroxisome proliferator-activated receptor (PPAR)delta is a ligand-activated transcription factor that affects oncogenesis in conjunction with beta-catenin. We used a carcinogenic H pylori strain to define the role of microbial virulence constituents and PPAR delta 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 PPAR delta 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. PPAR delta and Ki67 expression were determined by immunohistochemical analysis of human biopsies and rodent gastric mucosa. RESULTS: H pylori induced beta-catenin- and p120-dependent expression and activation of PPAR delta in gastric epithelial cells, which were mediated by the cag secretion system substrates CagA and peptidoglycan. H pylori stimulated proliferation in vitro, which required PPAR delta-mediated activation of cyclin E1; H pylori did not induce expression of cyclin E1 in a genetic model of PPAR delta deficiency. PPAR delta expression and proliferation in rodent and human gastric tissue was selectively induced by cag(+) strains and PPAR delta levels normalized after eradication of H pylori. CONCLUSIONS: The H pylori cag secretion system activates beta-catenin, p120, and PPAR delta, which promote gastric epithelial cell proliferation via activation of cyclin E1. PPAR delta might contribute to gastric adenocarcinoma development in humans.