期刊
GASTROENTEROLOGY
卷 141, 期 2, 页码 553-564出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2011.05.004
关键词
Stomach Cancer; Mongolian Gerbils; Signaling; Bacteria
资金
- National Institutes of Health [CA 77955, DK 58587, CA 028842, AI 039657, AI 068009]
- Department of Veterans Affairs
- [CA 116087]
- [DK 058404]
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.
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