Feng Guoxun, Zhang Yan, Yuan Huisheng, Bai Rixing, Zheng Jianwei, Zhang Jinqian, Song Maomin
Department of General Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
Mol Med Rep. 2014 Jan;9(1):109-17. doi: 10.3892/mmr.2013.1772. Epub 2013 Nov 4.
Trefoil factor 1 (TFF1) is a tumor suppressor gene that encodes a peptide belonging to the trefoil factor family of protease‑resistant peptides. Although TFF1 expression is frequently lost in gastric carcinomas (GCs), the tumorigenic pathways that are affected have yet to be determined. The aim of the current study was to identify the mechanism(s) by which the TFF1 gene is regulated in gastric carcinogenesis. In this study, TFF1 was shown to be silenced or downregulated in gastric tumor tissue compared with matched non‑cancerous tissue. In addition, human gastric cells weakly expressed TFF1. The hypermethylation status in the promoter CpG islands appeared to be correlated with TFF1 expression levels in gastric cell lines or specimen tissue. Further molecular analysis indicated that the CpG islands play a role in the promoter activity of the TFF1 gene. The expression of TFF1 and DNA methylation of its promoter affected cell proliferation and apoptosis. The expression of TFF1 in gastric cell lines was restored with a demethylating agent, 5‑azacytidine. Low expression of TFF1 in gastric cell lines and cancer tissue is associated with TP 53. In conclusion, the current study demonstrates that DNA methylation is a key mechanism of silencing TFF1 expression in human gastric cells and TFF1 gene hypermethylation of the CpG islands is a potential biomarker for GC.
三叶因子1（TFF1）是一种肿瘤抑制基因，编码一种属于三叶因子家族的抗蛋白酶肽。尽管TFF1表达在胃癌（GC）中经常缺失，但受影响的致瘤途径尚未确定。本研究的目的是确定TFF1基因在胃癌发生过程中的调控机制。在本研究中，与配对的非癌组织相比，TFF1在胃肿瘤组织中显示为沉默或下调。此外，人胃细胞弱表达TFF1。启动子CpG岛的高甲基化状态似乎与胃细胞系或标本组织中的TFF1表达水平相关。进一步的分子分析表明，CpG岛在TFF1基因的启动子活性中起作用。TFF1的表达及其启动子的DNA甲基化影响细胞增殖和凋亡。用去甲基化剂5-氮杂胞苷可恢复胃细胞系中TFF1的表达。胃细胞系和癌组织中TFF1的低表达与TP 53相关。总之，本研究表明DNA甲基化是人类胃细胞中TFF1表达沉默的关键机制，CpG岛的TFF1基因高甲基化是GC的潜在生物标志物。
