Folic acid increases global DNA methylation and reduces inflammation to prevent Helicobacter-associated gastric cancer in mice.

Abstract:

BACKGROUND & AIMS: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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Gonda TA,Kim YI,Salas MC,Gamble MV,Shibata W,Muthupalani S,Sohn KJ,Abrams JA,Fox JG,Wang TC,Tycko B

doi

10.1053/j.gastro.2011.12.058

subject

Has Abstract

pub_date

2012-04-01 00:00:00

pages

824-833.e7

issue

4

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(12)00029-7

journal_volume

142

pub_type

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