Antagonizing roles of SHP1 in the pathogenesis of Helicobacter pylori infection
Si Chen1, Huilin Zhao1, Yue Tian1,2
1Binzhou Medical University, Yantai, China.
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.
Insights
The protein tyrosine phosphatase SHP1 acts antagonistically to Helicobacter pylori infection by inhibiting key signaling pathways and reducing cell damage. Activating SHP1 with sorafenib demonstrated a significant curative effect against H. pylori pathogenesis in vitro and in vivo.
Area of Science:
- Cell Biology
- Molecular Biology
- Microbiology
Background:
- SHP1 (SH2 domain-containing phosphatase-1) is recognized as a tumor suppressor.
- Its antagonistic role in Helicobacter pylori pathogenesis has been suggested but the precise mechanisms required further elucidation.
Purpose of the Study:
- To investigate the detailed molecular mechanisms by which SHP1 antagonizes Helicobacter pylori pathogenesis.
- To evaluate the therapeutic potential of SHP1 activation against H. pylori infection.
Main Methods:
- Cellular localization of SHP1 was assessed via immunofluorescence following H. pylori infection.
- SHP1 overexpression and knockdown were employed to study its role in H. pylori-infected cells.
- Cell migration, invasion, IL-8 secretion, and hummingbird-like cell morphology were analyzed.
- Key signaling pathways (JAK2/STAT3, PI3K/Akt, ERK) and NF-κB activation were examined by immunoblotting.
- A mouse infection model was utilized to evaluate gastric pathological changes.
Main Results:
- H. pylori infection induced a shift in SHP1 localization from the cytoplasm to the cell membrane.
- SHP1 inhibited H. pylori-induced activation of JAK2/STAT3, PI3K/Akt, and NF-κB pathways, consequently reducing epithelial-mesenchymal transition (EMT), migration, invasion, and IL-8 secretion.
- SHP1 dephosphorylated CagA, inhibiting CagA-SHP2 complex formation, ERK phosphorylation, and hummingbird-like cell formation.
- In vivo, SHP1 activation with sorafenib significantly attenuated gastric pathology, IL-8 secretion, and EMT progression.
Conclusions:
- SHP1 antagonizes H. pylori pathogenesis by suppressing critical signaling pathways including JAK2/STAT3, PI3K/Akt, and NF-κB.
- SHP1 effectively reduces H. pylori-induced cell migration, invasion, IL-8 secretion, EMT, and hummingbird-like cellular changes.
- SHP1 activation represents a promising therapeutic strategy against H. pylori infection.
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