title: Helicobacter pylori infection promotes methylation and silencing of trefoil factor 2, leading to gastric tumor development in mice and humans.
abstract: OBJECTIVE
  Trefoil factors (TFFs) regulate mucosal repair and suppress tumor formation in the stomach. Tff1 deficiency results in gastric cancer, whereas Tff2 deficiency increases gastric inflammation. TFF2 expression is frequently lost in gastric neoplasms, but the nature of the silencing mechanism and associated impact on tumorigenesis have not been determined.
  
  
  METHODS
  We investigated the epigenetic silencing of TFF2 in gastric biopsy specimens from individuals with Helicobacter pylori-positive gastritis, intestinal metaplasia, gastric cancer, and disease-free controls. TFF2 function and methylation were manipulated in gastric cancer cell lines. The effects of Tff2 deficiency on tumor growth were investigated in the gp130(F/F) mouse model of gastric cancer.
  
  
  RESULTS
  In human tissue samples, DNA methylation at the TFF2 promoter began at the time of H pylori infection and increased throughout gastric tumor progression. TFF2 methylation levels were inversely correlated with TFF2 messenger RNA levels and could be used to discriminate between disease-free controls, H pylori-infected, and tumor tissues. Genome demethylation restored TFF2 expression in gastric cancer cell lines, so TFF2 silencing requires methylation. In Tff2-deficient gp130(F/F)/Tff2(-/-) mice, proliferation of mucosal cells and release of T helper cell type-1 (Th-1) 1 cytokines increased, whereas expression of gastric tumor suppressor genes and Th-2 cytokines were reduced, compared with gp130(F/F)controls. The fundus of gp130(F/F)/Tff2(-/-) mice displayed glandular atrophy and metaplasia, indicating accelerated preneoplasia. Experimental H pylori infection in wild-type mice reduced antral expression of Tff2 by increased promoter methylation.
  
  
  CONCLUSIONS
  TFF2 negatively regulates preneoplastic progression and subsequent tumor development in the stomach, a role that is subverted by promoter methylation during H pylori infection.
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Victoria.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Peterson
authors.forename: Trevelyan R
authors.initials: TR
authors.lastname: Menheniott
authors.forename: Louise
authors.initials: L
authors.lastname: O'Connor
authors.forename: Anna K
authors.initials: AK
authors.lastname: Walduck
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kawakami
authors.forename: Toshinari
authors.initials: T
authors.lastname: Minamoto
authors.forename: Eng Kok
authors.initials: EK
authors.lastname: Ong
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Louise M
authors.initials: LM
authors.lastname: Judd
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Giraud
mesh_terms: D000818:Animals; D001284:Atrophy; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000235:genetics; D019175:DNA Methylation / Q000502:physiology; D057890:Epigenomics; D005756:Gastritis / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D016481:Helicobacter Infections / Q000235:genetics* / Q000473:pathology; D016480:Helicobacter pylori; D006801:Humans; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009077:Mucins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D010455:Peptides / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D018417:Th1 Cells / Q000502:physiology; D000071164:Trefoil Factor-2
chemical_list: C494200:Il6st protein, mouse; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; C000604007:TFF2 protein, human; C481546:TFF2 protein, mouse; D000071164:Trefoil Factor-2; D050822:Cytokine Receptor gp130
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