DKK1 is epigenetically downregulated by promoter methylation and inhibits bile acid-induced gastric intestinal metaplasia.
DKK1 is epigenetically downregulated by promoter methylation and inhibits bile acid-induced gastric intestinal metaplasia.
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DOI：
10.1016/j.bbrc.2019.12.109
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发表时间：
2020-01
影响因子：
3.1
通讯作者：
Wenquan Lu;Z. Ni;Mingfu Tong;Shuqin Jiang;Jian Zhang;Chenchen Feng;Chuan Han;Ting Yuan;Na Wang;J. Zhao;Nina Sun;Caifang Liu;Q. Jia;Qiong Wu;H. Ning;Yongquan Shi
中科院分区：
文献类型：
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作者：
Wenquan Lu;Z. Ni;Mingfu Tong;Shuqin Jiang;Jian Zhang;Chenchen Feng;Chuan Han;Ting Yuan;Na Wang;J. Zhao;Nina Sun;Caifang Liu;Q. Jia;Qiong Wu;H. Ning;Yongquan Shi
Dickkopf相关蛋白1(Dkk1)作为Wnt信号的抑制因子，在胃癌发生发展中起重要作用。胃肠上皮化生(GIM)是一种重要的胃癌前病变，可被胆酸反流和慢性炎症所激活。然而，Dkk1在胆汁酸诱导的GIM中的确切作用机制尚未完全阐明。本研究旨在探讨Dkk1在GIM发生发展过程中的表观遗传学改变及其生物学功能。在本研究中，胆汁酸可以诱导胃上皮细胞中肠道标志物的表达，而Dkk1在胆汁酸刺激下表达下调。定量逆转录聚合酶链式反应和免疫组织化学染色显示，牙周炎组织中Dkk1的mRNA和蛋白表达水平降低。令人惊讶的是，Dkk1启动子的甲基化在GIM组织中增加，我们在GIM组织中发现了Dkk1启动子的28个差异甲基化位点。胆汁酸可诱导胃上皮细胞Dkk1启动子部分甲基化，5-氮杂氮可增加Dkk1的表达，降低肠道标志物的表达。综上所述，Dkk1基因启动子甲基化和下调可能在GIM，尤其是胆汁酸诱导的GIM的发生发展中起重要作用。
Dickkopf-related protein 1 (DKK1) is essential to gastric cancer as an inhibitor of Wnt signaling. Gastric intestinal metaplasia (GIM) is an important precancerous lesion of gastric cancer that can be activated by bile acid reflux and chronic inflammation. However, the exact mechanism of DKK1 in bile acid-induced GIM has not been completely elucidated. We aimed to explore the epigenetic alterations and biological functions of DKK1 in the development of GIM. In the present study, bile acid was found to induce the expression of intestinal markers in gastric epithelial cells, whereas DKK1 was downregulated in response to bile acid stimulation. The mRNA and protein expression levels of DKK1 were decreased in GIM tissues as evidenced by qRT-PCR and immunohistochemical staining. Surprisingly, the methylation of the DKK1 promoter increased in GIM tissues, and we discovered 28 differential methylation sites of the DKK1 promoter in GIM tissues. Bile acid was able to induce the partial methylation of the DKK1 promoter, while 5-aza could increase DKK1 expression as well as decrease intestinal markers expression in gastric epithelial cells. In conclusion, the promoter methylation and downregulation of DKK1 might play important roles in the development of GIM, especially bile acid-induced GIM.