Inhibition of gastric carcinogenesis by the hormone gastrin is mediated by suppression of TFF1 epigenetic silencing.
Inhibition of gastric carcinogenesis by the hormone gastrin is mediated by suppression of TFF1 epigenetic silencing.
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DOI：
10.1053/j.gastro.2010.11.037
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发表时间：
2011-03
期刊：
影响因子：
29.4
通讯作者：
Wang TC
中科院分区：
文献类型：
--
作者：
Tomita H;Takaishi S;Menheniott TR;Yang X;Shibata W;Jin G;Betz KS;Kawakami K;Minamoto T;Tomasetto C;Rio MC;Lerkowit N;Varro A;Giraud AS;Wang TC
表观遗传学改变与人类患者的实地癌变相关，但缺乏来自实验模型的证据表明特定的表观遗传学改变可以引发癌症。虽然激素与癌症风险有关，但其机制尚未确定。肽类激素胃泌素对胃窦癌的发生具有抑制作用。在高胃泌素血症（INS-GAS）、胃泌素缺陷（GAS-/-）、Tff 1缺陷（Tff 1 +/-）和野生型（WT）小鼠中研究了N-甲基-N-亚硝基脲（MNU）依赖性胃癌。在体外和体内评价了三叶因子1（TFF 1）肿瘤抑制基因的表观遗传学改变。人胃窦型胃癌表现出进行性TFF 1抑制和启动子高甲基化。用MNU处理的小鼠表现出一种场缺陷，其特征在于与上皮细胞中Tff 1启动子处的组蛋白H3赖氨酸9（H3 K9）甲基化和H3去乙酰化相关的广泛Tff 1抑制。在MNU诱导的晚期癌症中，观察到Tff 1启动子的DNA甲基化。通过螺杆菌感染，MNU处理的小鼠的肿瘤诱导和Tff 1抑制增加。高胃泌素血症抑制MNU依赖性肿瘤的发生和发展，其方式与Tff 1的基因沉默和表观遗传学改变相关。与此相反，纯合子胃泌素缺陷和杂合子Tff 1缺陷小鼠表现出增强的MNU依赖性领域的缺陷和癌症的启动与WT小鼠相比。在胃癌细胞中，胃泌素刺激部分逆转了TFF 1启动子中的表观遗传沉默。胃窦癌的发生与TFF 1的进行性表观遗传沉默有关，TFF 1可被激素胃泌素抑制。
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. 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. 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 (H3K9) 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. Antral gastric cancer initiation is associated with progressive epigenetic silencing of TFF1, which can be suppressed by the hormone gastrin.
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