Antagonizing roles of SHP1 in the pathogenesis of Helicobacter pylori infection

IF 4.3 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Helicobacter Pub Date : 2024-03-12 DOI:10.1111/hel.13066

Si Chen, Huilin Zhao, Yue Tian, Qianwen Wu, Jianhui Zhang, Shuzhen Liu, Ying Zhang, Yulong Wu, Boqing Li, Shu Chen, Zhiqiang Wang, Ruoyu Xiao, Xiaofei Ji

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Abstract

Background

SHP1 has been documented as a tumor suppressor and it was thought to play an antagonistic role in the pathogenesis of Helicobacter pylori infection. In this study, the exact mechanism of this antagonistic action was studied.

Materials and Methods

AGS, MGC803, and GES-1 cells were infected with H. pylori, intracellular distribution changes of SHP1 were first detected by immunofluorescence. SHP1 overexpression and knockdown were then constructed in these cells to investigate its antagonistic roles in H. pylori infection. Migration and invasion of infected cells were detected by transwell assay, secretion of IL-8 was examined via ELISA, the cells with hummingbird-like alteration were determined by microexamination, and activation of JAK2/STAT3, PI3K/Akt, and ERK pathways were detected by immunoblotting. Mice infection model was established and gastric pathological changes were evaluated. Finally, the SHP1 activator sorafenib was used to analyze the attenuating effect of SHP1 activation on H. pylori pathogenesis in vitro and in vivo.

Results

The sub-localization of SHP1 changed after H. pylori infection, specifically that the majority of the cytoplasmic SHP1 was transferred to the cell membrane. SHP1 inhibited H. pylori-induced activation of JAK2/STAT3 pathway, PI3K/Akt pathway, nuclear translocation of NF-κB, and then reduced EMT, migration, invasion, and IL-8 secretion. In addition, SHP1 inhibited the formation of CagA-SHP2 complex by dephosphorylating phosphorylated CagA, reduced ERK phosphorylation and the formation of CagA-dependent hummingbird-like cells. In the mice infection model, gastric pathological changes were observed and increased IL-8 secretion, indicators of cell proliferation and EMT progression were also detected. By activating SHP1 with sorafenib, a significant curative effect against H. pylori infection was obtained in vitro and in vivo.

Conclusions

SHP1 plays an antagonistic role in H. pylori pathogenesis by inhibiting JAK2/STAT3 and PI3K/Akt pathways, NF-κB nuclear translocation, and CagA phosphorylation, thereby reducing cell EMT, migration, invasion, IL-8 secretion, and hummingbird-like changes.

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SHP1 在幽门螺旋杆菌感染发病机制中的拮抗作用。

背景：SHP1是一种肿瘤抑制因子，被认为在幽门螺杆菌感染的发病机制中起着拮抗作用。本研究对这种拮抗作用的确切机制进行了研究：用幽门螺杆菌感染 AGS、MGC803 和 GES-1 细胞，首先用免疫荧光法检测 SHP1 在细胞内的分布变化。然后在这些细胞中构建 SHP1 的过表达和敲除，以研究其在幽门螺杆菌感染中的拮抗作用。通过Transwell试验检测感染细胞的迁移和侵袭，通过ELISA检测IL-8的分泌，通过显微镜检查确定蜂鸟样改变的细胞，通过免疫印迹检测JAK2/STAT3、PI3K/Akt和ERK通路的激活。建立小鼠感染模型并评估胃病理变化。最后，利用SHP1激活剂索拉非尼分析了SHP1激活对幽门螺杆菌体内外发病机制的抑制作用：结果：幽门螺杆菌感染后，SHP1的亚定位发生了变化，特别是大部分细胞质中的SHP1转移到了细胞膜上。SHP1可抑制幽门螺杆菌诱导的JAK2/STAT3通路、PI3K/Akt通路的激活和NF-κB的核转位，进而减少EMT、迁移、侵袭和IL-8的分泌。此外，SHP1 还能通过使磷酸化的 CagA 去磷酸化来抑制 CagA-SHP2 复合物的形成，减少 ERK 磷酸化和 CagA 依赖性蜂鸟样细胞的形成。在小鼠感染模型中，观察到胃部病理变化，IL-8 分泌增加，细胞增殖和 EMT 进展指标也被检测到。通过索拉非尼激活 SHP1，可在体外和体内对幽门螺杆菌感染产生显著疗效：结论：SHP1通过抑制JAK2/STAT3和PI3K/Akt通路、NF-κB核转位和CagA磷酸化，从而减少细胞的EMT、迁移、侵袭、IL-8分泌和蜂鸟样变化，在幽门螺杆菌发病机制中发挥拮抗作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Helicobacter 医学-微生物学

CiteScore

8.40

自引率

9.10%

发文量

审稿时长

2 months

期刊介绍： Helicobacter is edited by Professor David Y Graham. The editorial and peer review process is an independent process. Whenever there is a conflict of interest, the editor and editorial board will declare their interests and affiliations. Helicobacter recognises the critical role that has been established for Helicobacter pylori in peptic ulcer, gastric adenocarcinoma, and primary gastric lymphoma. As new helicobacter species are now regularly being discovered, Helicobacter covers the entire range of helicobacter research, increasing communication among the fields of gastroenterology; microbiology; vaccine development; laboratory animal science.