Inhibition of gastric carcinogenesis by the hormone gastrin is mediated by suppression of TFF1 epigenetic silencing

Gastroenterology. 2011 Mar;140(3):879-91. doi: 10.1053/j.gastro.2010.11.037. Epub 2010 Nov 25.


Background & aims: Epigenetic alterations have been correlated with field cancerization in human patients, but evidence from experimental models that specific epigenetic changes can initiate cancer has been lacking. Although hormones have been associated with cancer risk, the mechanisms have not been determined. The peptide hormone gastrin exerts a suppressive effect on antral gastric carcinogenesis.

Methods: N-methyl-N-nitrosourea (MNU)-dependent gastric cancer was investigated in hypergastrinemic (INS-GAS), gastrin-deficient (GAS(-/-)), Tff1-deficient (Tff1(+/-)), and wild-type (WT) mice. Epigenetic alterations of the trefoil factor 1 (TFF1) tumor suppressor gene were evaluated in vitro and in vivo.

Results: Human intestinal-type gastric cancers in the antrum exhibited progressive TFF1 repression and promoter hypermethylation. Mice treated with MNU exhibited a field defect characterized by widespread Tff1 repression associated with histone H3 lysine 9 methylation and H3 deacetylation at the Tff1 promoter in epithelial cells. In MNU-induced advanced cancers, DNA methylation at the Tff1 promoter was observed. Tumor induction and Tff1 repression were increased in MNU-treated mice by Helicobacter infection. Hypergastrinemia suppressed MNU-dependent tumor initiation and progression in a manner that correlated with gene silencing and epigenetic alterations of Tff1. In contrast, homozygous gastrin-deficient and heterozygous Tff1-deficient mice showed enhanced MNU-dependent field defects and cancer initiation compared with WT mice. In gastric cancer cells, gastrin stimulation partially reversed the epigenetic silencing in the TFF1 promoter.

Conclusions: Initiation of antral gastric cancer is associated with progressive epigenetic silencing of TFF1, which can be suppressed by the hormone gastrin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Chromatin Assembly and Disassembly
  • DNA Methylation
  • Disease Models, Animal
  • Female
  • Gastrins / deficiency
  • Gastrins / genetics
  • Gastrins / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing*
  • Helicobacter Infections / genetics
  • Helicobacter Infections / metabolism
  • Helicobacter Infections / microbiology
  • Helicobacter felis / pathogenicity
  • Histones / metabolism
  • Humans
  • Male
  • Methylnitrosourea
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Peptides / deficiency
  • Peptides / genetics*
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / microbiology
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / prevention & control*
  • Time Factors
  • Transfection
  • Trefoil Factor-1
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism


  • Gastrins
  • Histones
  • Peptides
  • RNA, Messenger
  • TFF1 protein, human
  • Tff1 protein, mouse
  • Trefoil Factor-1
  • Tumor Suppressor Proteins
  • Methylnitrosourea