title: Folic acid increases global DNA methylation and reduces inflammation to prevent Helicobacter-associated gastric cancer in mice.
abstract: OBJECTIVE
  Previous studies have suggested that dietary folic acid (FA) can protect against certain types of cancers. However, the findings have varied, and the mechanisms by which FA exerts chemopreventive effects remain to be clarified. We examined the effects of FA supplementation on DNA methylation, gene expression, and gastric dysplasia in a transgenic mouse model that is etiologically and histologically well matched with human gastric cancers.
  
  
  METHODS
  Hypergastrinemic mice infected with Helicobacter felis were studied at multiple stages of gastric dysplasia and early cancer with FA supplementation initiated both at weaning and later in life. Global DNA methylation was assessed by a methylation sensitive cytosine incorporation assay, bisulfite pyrosequencing of B1 repetitive elements, and immunohistochemistry with anti-5-methylcytosine. We also profiled gene expression in the same tissues.
  
  
  RESULTS
  We found a decrease in global DNA methylation and tissue folate and an increase in serum homocysteine with progression of gastric dysplasia. FA supplementation prevented this loss of global DNA methylation and markedly reduced gastric dysplasia and mucosal inflammation. FA protected against the loss of global DNA methylation both in the dysplastic gastric epithelial cells and in gastric stromal myofibroblasts. In addition, FA supplementation had an anti-inflammatory effect, as indicated by expression profiling and immunohistochemistry for lymphocyte markers.
  
  
  CONCLUSIONS
  We conclude that FA supplementation is chemopreventive in this model of Helicobacter-associated gastric cancer. The beneficial effect of FA is likely due to its ability to prevent global loss of methylation and suppress inflammation.
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York 10032, USA. tg2214@columbia.edu
authors.forename: Tamas A
authors.initials: TA
authors.lastname: Gonda
authors.forename: Young-In
authors.initials: YI
authors.lastname: Kim
authors.forename: Martha C
authors.initials: MC
authors.lastname: Salas
authors.forename: Mary V
authors.initials: MV
authors.lastname: Gamble
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Sohn
authors.forename: Julian A
authors.initials: JA
authors.lastname: Abrams
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tycko
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects*; D004195:Disease Models, Animal; D005492:Folic Acid / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000235:genetics / Q000378:metabolism; D005756:Gastritis / Q000097:blood / Q000235:genetics / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D016481:Helicobacter Infections / Q000097:blood / Q000150:complications / Q000235:genetics / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D044922:Helicobacter felis / Q000472:pathogenicity*; D006710:Homocysteine / Q000097:blood; D007150:Immunohistochemistry; D008214:Lymphocytes / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D013270:Stomach / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology; D013274:Stomach Neoplasms / Q000097:blood / Q000235:genetics / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D017154:Stromal Cells / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; D005755:Gastrins; D006710:Homocysteine; D005492:Folic Acid