Antagonizing roles of SHP1 in the pathogenesis of Helicobacter pylori infection

Author:

Chen Si1,Zhao Huilin1,Tian Yue12,Wu Qianwen1,Zhang Jianhui1,Liu Shuzhen1,Zhang Ying1,Wu Yulong1,Li Boqing1,Chen Shu1,Wang Zhiqiang1,Xiao Ruoyu1,Ji Xiaofei1

Affiliation:

1. Binzhou Medical University Yantai China

2. Binzhou People's Hospital Binzhou China

Abstract

AbstractBackgroundSHP1 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 MethodsAGS, 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.ResultsThe 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.ConclusionsSHP1 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.

Funder

Natural Science Foundation of Shandong Province

Taishan Scholar Project of Shandong Province

Publisher

Wiley

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