Inhibition of gastric carcinogenesis by the hormone gastrin is mediated by suppression of TFF1 epigenetic silencing.
OBJECTIVE
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.
Division of Digestive and Liver Disease, Irving Cancer Research Center, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
Hiroyuki
H
Tomita
Shigeo
S
Takaishi
Trevelyan R
TR
Menheniott
Xiangdong
X
Yang
Wataru
W
Shibata
Guangchun
G
Jin
Kelly S
KS
Betz
Kazuyuki
K
Kawakami
Toshinari
T
Minamoto
Catherine
C
Tomasetto
Marie-Christine
MC
Rio
Nataporn
N
Lerkowit
Andrea
A
Varro
Andrew S
AS
Giraud
Timothy C
TC
Wang
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D042002:Chromatin Assembly and Disassembly; D019175:DNA Methylation; D004195:Disease Models, Animal; D005260:Female; D005755:Gastrins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D044922:Helicobacter felis / Q000472:pathogenicity; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008770:Methylnitrosourea; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000172:deficiency / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D014162:Transfection; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D005755:Gastrins; D006657:Histones; D010455:Peptides; D012333:RNA, Messenger; C051838:TFF1 protein, human; C472724:Tff1 protein, mouse; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D008770:Methylnitrosourea