Helicobacter pylori CagA induces tumor suppressor gene hypermethylation by upregulating DNMT1 via AKT-NFκB pathway in gastric cancer development.
Helicobacter pylori CagA induces tumor suppressor gene hypermethylation by upregulating DNMT1 via AKT-NFκB pathway in gastric cancer development.
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幽门螺杆菌 CagA 通过 AKT-NF kappa B 通路上调 DNMT1 诱导抑癌基因高甲基化
DOI：
10.18632/oncotarget.7125
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发表时间：
2016-03-01
期刊：
影响因子：
--
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Zhang BG;Hu L;Zang MD;Wang HX;Zhao W;Li JF;Su LP;Shao Z;Zhao X;Zhu ZG;Yan M;Liu B
抑癌基因提示子中 CpG 岛的甲基化是幽门螺杆菌 (HP) 相关胃癌 (GC) 中最具特征性的异常之一。在这里，我们研究了 HP 诱导的 GC 发育中肿瘤抑制基因高甲基化的致病和分子机制。我们发现临床标本、HP感染的C57小鼠胃组织以及CagA转染或HP感染处理的GC细胞系中以MGMT为代表的抑癌基因高甲基化与CagA呈正相关。 CagA 增强 PDK1 和 AKT 相互作用并增加 AKT 磷酸化。 P-AKT 随后激活 NFκB，然后与 DNMT1 启动子结合并增加其表达。最后，上调的DNMT1促进了以MGMT为代表的抑癌基因高甲基化。总之，CagA 通过 AKT-NFκB 通路刺激 DNMT1 表达，从而增加抑癌基因的高甲基化。
Methylation of CpG islands in tumor suppressor gene prompter is one of the most characteristic abnormalities in Helicobacter pylori (HP)-associated gastric carcinoma (GC). Here, we investigated the pathogenic and molecular mechanisms underlying hypermethylation of tumor suppressor genes in HP induced GC development. We found that tumor suppressor genes hypermethylation, represented by MGMT, positively correlated with CagA in clinical specimens, gastric tissues from HP infected C57 mice and GC cell lines transfected by CagA or treated by HP infection. CagA enhanced PDK1 and AKT interaction and increased AKT phosphorylation. The P-AKT subsequent activated NFκB, which then bound to DNMT1 promoter and increased its expression. Finally, the upregulated DNMT1 promoted tumor suppressor genes hypermethylation with MGMT as a representative. In conclusion, CagA increased tumor suppressor genes hypermethylation via stimulating DNMT1 expression through the AKT-NFκB pathway.