Division of Gastroenterology, Department of Internal Medicine and Gastrointestinal Cancer Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
Division of Gastroenterology, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
Gastric Cancer. 2018 Mar;21(2):237-248. doi: 10.1007/s10120-017-0741-6. Epub 2017 Jun 22.
This study aimed to investigate the changes in the promoter methylation and gene expression of multiple Wnt antagonists between the chronic infection and eradication of Helicobacter pylori (H. pylori) in gastric carcinogenesis.
The levels of methylation and corresponding mRNA expression of seven Wnt antagonist genes (SFRP1, -2, -5, DKK1, -2, -3, WIF1) were compared among the patients with H. pylori-positive gastric cancers (GCs), and H. pylori-positive and H. pylori-negative controls, by quantitative MethyLight assay and real-time reverse transcription (RT)-polymerase chain reaction (PCR), respectively. The changes of the methylation and expression levels of the genes were also compared between the H. pylori eradication and H. pylori-persistent groups 1 year after endoscopic resection of GCs.
The methylation levels of SFRP and DKK family genes were significantly increased in the patients with H. pylori-positive GCs and followed by H. pylori-positive controls compared with H. pylori-negative controls (P < 0.001). SFRP1, -2, and DKK3 gene expression was stepwise downregulated from H. pylori-negative controls, H. pylori-positive controls, and to H. pylori-positive GCs (P < 0.05). Among the Wnt antagonists, only the degrees of methylation and downregulation of DKK3 were significantly reduced after H. pylori eradication (P < 0.05).
Epigenetic silencing of SFRP and DKK family genes may facilitate the formation of an epigenetic field during H. pylori-associated gastric carcinogenesis. The epigenetic field may not be reversed even after H. pylori eradication except by DKK3 methylation.
本研究旨在探讨幽门螺杆菌（H. pylori）慢性感染和根除在胃癌发生过程中多个 Wnt 拮抗剂启动子甲基化和基因表达的变化。
采用定量 MethyLight 检测和实时逆转录（RT）-聚合酶链反应（PCR）分别比较 H. pylori 阳性胃癌患者、H. pylori 阳性和 H. pylori 阴性对照者中 7 个 Wnt 拮抗剂基因（SFRP1、-2、-5、DKK1、-2、-3、WIF1）的甲基化和相应 mRNA 表达水平。在胃癌内镜切除 1 年后，还比较了 H. pylori 根除组和 H. pylori 持续组中基因甲基化和表达水平的变化。
与 H. pylori 阴性对照组相比，H. pylori 阳性胃癌患者和 H. pylori 阳性对照组中 SFRP 和 DKK 家族基因的甲基化水平显著升高（P<0.001）。SFRP1、-2 和 DKK3 基因表达水平从 H. pylori 阴性对照组、H. pylori 阳性对照组到 H. pylori 阳性胃癌患者呈逐步下调（P<0.05）。在 Wnt 拮抗剂中，只有 DKK3 的甲基化和下调程度在 H. pylori 根除后显著降低（P<0.05）。
SFRP 和 DKK 家族基因的表观遗传沉默可能有助于 H. pylori 相关胃癌发生过程中形成表观遗传场。即使在 H. pylori 根除后，除了 DKK3 甲基化外，这种表观遗传场可能不会逆转。
