4.8 Article

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

Journal

GASTROENTEROLOGY
Volume 141, Issue 2, Pages 553-564

Publisher

W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2011.05.004

Keywords

Stomach Cancer; Mongolian Gerbils; Signaling; Bacteria

Funding

  1. National Institutes of Health [CA 77955, DK 58587, CA 028842, AI 039657, AI 068009]
  2. Department of Veterans Affairs
  3. [CA 116087]
  4. [DK 058404]

Ask authors/readers for more resources

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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available