Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Victoria.
Gastroenterology. 2010 Dec;139(6):2005-17. doi: 10.1053/j.gastro.2010.08.043. Epub 2010 Aug 27.
BACKGROUND & AIMS: Trefoil factors (TFFs) regulate mucosal repair and suppress tumor formation in the stomach. Tff1 deficiency results in gastric cancer, whereas Tff2 deficiency increases gastric inflammation. TFF2 expression is frequently lost in gastric neoplasms, but the nature of the silencing mechanism and associated impact on tumorigenesis have not been determined.
We investigated the epigenetic silencing of TFF2 in gastric biopsy specimens from individuals with Helicobacter pylori-positive gastritis, intestinal metaplasia, gastric cancer, and disease-free controls. TFF2 function and methylation were manipulated in gastric cancer cell lines. The effects of Tff2 deficiency on tumor growth were investigated in the gp130(F/F) mouse model of gastric cancer.
In human tissue samples, DNA methylation at the TFF2 promoter began at the time of H pylori infection and increased throughout gastric tumor progression. TFF2 methylation levels were inversely correlated with TFF2 messenger RNA levels and could be used to discriminate between disease-free controls, H pylori-infected, and tumor tissues. Genome demethylation restored TFF2 expression in gastric cancer cell lines, so TFF2 silencing requires methylation. In Tff2-deficient gp130(F/F)/Tff2(-/-) mice, proliferation of mucosal cells and release of T helper cell type-1 (Th-1) 1 cytokines increased, whereas expression of gastric tumor suppressor genes and Th-2 cytokines were reduced, compared with gp130(F/F)controls. The fundus of gp130(F/F)/Tff2(-/-) mice displayed glandular atrophy and metaplasia, indicating accelerated preneoplasia. Experimental H pylori infection in wild-type mice reduced antral expression of Tff2 by increased promoter methylation.
TFF2 negatively regulates preneoplastic progression and subsequent tumor development in the stomach, a role that is subverted by promoter methylation during H pylori infection.
三叶因子（TFFs）调节胃黏膜修复并抑制肿瘤形成。Tff1 缺失导致胃癌，而 Tff2 缺失则增加胃炎症。TFF2 的表达在胃肿瘤中经常丢失，但沉默机制的性质及其对肿瘤发生的影响尚未确定。
我们研究了幽门螺杆菌阳性胃炎、肠上皮化生、胃癌和无疾病对照个体胃活检标本中 TFF2 的表观遗传沉默。在胃癌细胞系中操纵 TFF2 功能和甲基化。在 gp130(F/F)胃癌小鼠模型中研究了 Tff2 缺失对肿瘤生长的影响。
在人类组织样本中，TFF2 启动子的 DNA 甲基化始于 H. pylori 感染时，并随着胃肿瘤进展而增加。TFF2 甲基化水平与 TFF2 信使 RNA 水平呈负相关，可用于区分无疾病对照、H. pylori 感染和肿瘤组织。基因组去甲基化可恢复胃癌细胞系中的 TFF2 表达，因此 TFF2 沉默需要甲基化。在 Tff2 缺失的 gp130(F/F)/Tff2(-/-)小鼠中，与 gp130(F/F)对照相比，黏膜细胞增殖和 Th1 细胞因子释放增加，而胃肿瘤抑制基因和 Th2 细胞因子的表达减少。gp130(F/F)/Tff2(-/-)小鼠的胃底显示出腺体萎缩和化生，表明前肿瘤进展加速。野生型小鼠的实验性 H. pylori 感染通过增加启动子甲基化导致胃窦 Tff2 的表达减少。
TFF2 负向调节胃的前肿瘤进展和随后的肿瘤发展，这种作用在 H. pylori 感染期间通过启动子甲基化而被颠覆。
