title: β-Catenin and p120 mediate PPARδ-dependent proliferation induced by Helicobacter pylori in human and rodent epithelia.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Toni A
authors.initials: TA
authors.lastname: Nagy
authors.forename: Lydia E
authors.initials: LE
authors.lastname: Wroblewski
authors.forename: Dingzhi
authors.initials: D
authors.lastname: Wang
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.forename: Alberto
authors.initials: A
authors.lastname: Delgado
authors.forename: Judith
authors.initials: J
authors.lastname: Romero-Gallo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Noto
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Israel
authors.forename: Seth R
authors.initials: SR
authors.lastname: Ogden
authors.forename: Pelayo
authors.initials: P
authors.lastname: Correa
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Cover
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
mesh_terms: D000230:Adenocarcinoma / Q000382:microbiology* / Q000473:pathology; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D051177:Catenins / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D019927:Cyclin E / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D005849:Gerbillinae; D016481:Helicobacter Infections / Q000378:metabolism*; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000382:microbiology* / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C475820:CCNE1 protein, human; D051177:Catenins; D019927:Cyclin E; D019394:Ki-67 Antigen; D015513:Oncogene Proteins; D047494:PPAR delta; D051176:beta Catenin; C080866:cagA protein, Helicobacter pylori; D000095002:Delta Catenin