Helicobacter pylori CagA promotes epithelial mesenchymal transition in gastric carcinogenesis via triggering oncogenic YAP pathway.
Helicobacter pylori CagA promotes epithelial mesenchymal transition in gastric carcinogenesis via triggering oncogenic YAP pathway.
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幽门螺杆菌CagA通过触发致癌YAP通路促进胃癌发生中的上皮间质转化
DOI：
10.1186/s13046-018-0962-5
复制
发表时间：
2018-11-22
期刊：
影响因子：
--
通讯作者：
Lu N
中科院分区：
文献类型：
--
作者：
Li N;Feng Y;Hu Y;He C;Xie C;Ouyang Y;Artim SC;Huang D;Zhu Y;Luo Z;Ge Z;Lu N
幽门螺杆菌 (H. pylori) 通过 T4SS 将癌蛋白 CagA 输送到胃上皮细胞中，并驱动多个致癌信号通路的激活。 YAP 是 Hippo 肿瘤抑制通路的核心效应子，在人类癌症中经常过度表达，表明其潜在的肿瘤促进作用。尽管 CagA 是幽门螺杆菌诱导的胃癌发生的偶然因素，但 CagA 和 YAP 通路之间的联系尚未确定。在这项工作中，我们研究了幽门螺杆菌 CagA 对致癌 YAP 途径的调节。通过免疫组织化学评估人胃活检中 YAP 和 E-钙粘蛋白的表达。幽门螺杆菌 PMSS1 cagA− 等基因突变株已生成。胃上皮细胞与幽门螺杆菌野生型cagA+菌株或同基因突变体共培养，并通过重组CagA表达进行处理。免疫荧光用于 YAP 定位。进行免疫印迹和定量 PCR 检查 YAP、下游效应子和上皮间质转化标志物的水平。维替泊芬和 siRNA 沉默用于抑制 YAP 活性。 YAP 在人类胃癌发生过程中显着上调。我们成功地产生了具有氯霉素抗性的PMSS1 CagA同基因突变株。我们的分析表明幽门螺杆菌感染诱导胃上皮细胞中的 YAP 和下游效应器。重要的是，7.13 和 PMSS1 菌株中 CagA 的敲除降低了幽门螺杆菌感染引起的 YAP 表达。此外，抑制 YAP 可抑制幽门螺杆菌感染诱导的上皮间质转化 (EMT)。我们的结果表明，幽门螺杆菌 CagA 作为致病蛋白可促进致癌 YAP 途径，从而有助于 EMT 和胃肿瘤的发生。这项研究为为什么 cagA+ 幽门螺杆菌感染与较高的胃癌发生风险相关提供了新的机制见解。本文的在线版本 (10.1186/s13046-018-0962-5) 包含补充材料，可供授权用户使用。
Helicobacter pylori (H. pylori) delivers oncoprotein CagA into gastric epithelial cells via the T4SS and drives activation of multiple oncogenic signalling pathways. YAP, a core effector of the Hippo tumour suppressor pathway, is frequently overexpressed in human cancers, suggesting its potential tumor-promoting role. Although CagA is a casual factor in H. pylori induced gastric carcinogenesis, the link between CagA and YAP pathway has not been identified. In this work, we investigated the regulation of oncogenic YAP pathway by H. pylori CagA. Expression of YAP and E-cadherin protein in human gastric biopsies were assessed by immunohistochemistry. H. pylori PMSS1 cagA− isogenic mutant strains were generated. Gastric epithelial cells were co-cultured with H. pylori wild-type cagA+ strains or isogenic mutants and were also treated by recombinant CagA expression. Immunofluorescence was performed for YAP localization. Immunoblot and quantitative PCR were performed for examining levels of YAP, downstream effectors and markers of epithelial-mesenchymal transition. Verteporfin and siRNA silencing were used to inhibit YAP activity. YAP is significantly upregulated in human gastric carcinogenesis. We generated PMSS1 CagA isogenic mutant strains with chloramphenicol resistance successfully. Our analysis indicated that H. pylori infection induced YAP and downstream effectors in gastric epithelial cells. Importantly, knockout of CagA in 7.13 and PMSS1 strains reduced the expression of YAP by H. pylori infection. Moreover, Inhibition of YAP suppressed H. pylori infection-induced Epithelial-mesenchymal transition (EMT). Our results indicated that H. pylori CagA as a pathogenic protein promotes oncogenic YAP pathway, which contributes to EMT and gastric tumorigenesis. This study provided a novel mechanistic insight into why cagA+ H. pylori infection is associated with a higher risk for the development of gastric cancer. The online version of this article (10.1186/s13046-018-0962-5) contains supplementary material, which is available to authorized users.
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DOI：
10.1158/1055-9965.epi-11-0548
发表时间：
2011-10
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Loh JT;Shaffer CL;Piazuelo MB;Bravo LE;McClain MS;Correa P;Cover TL
通讯作者：
Cover TL
影响因子：
12.2
作者：
Cover, Timothy L.;Peek, Richard M., Jr.
通讯作者：
Peek, Richard M., Jr.
模拟 VGLL4 功能的肽作为 YAP 拮抗剂治疗胃癌
影响因子：
50.3
作者：
Jiao, Shi;Wang, Huizhen;Zhou, Zhaocai
通讯作者：
Zhou, Zhaocai
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
TAZ 促进细胞增殖和上皮间质转化，并受 hippo 通路抑制
影响因子：
5.3
作者：
Lei, Qun-Ying;Zhang, Heng;Guan, Kun-Liang
通讯作者：
Guan, Kun-Liang