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More powerful dysregulation of Helicobacter pylori East Asian-type CagA on intracellular signalings

Year: 2024

Type: article

Abstract: Chronic infection by Helicobacter pylori strains expressing cytotoxin-associated gene A (CagA) are the strongest risk factor for gastric cancer. CagA can be classified into East Asian-type and Western-type (CagA E and CagA W ), with CagA E being more closely associated with gastric cancer. This study aimed to investigate the impact of CagA E on intracellular signaling pathways to explain its high oncogenicity. Mutant H. pylori strains expressing either CagA E or CagA W were generated by transforming CagA E/W -expression plasmid into CagA-deleted G27 strain (G27 ΔCagA ). In human gastric epithelial cells (GES-1) infection, CagA E induced more severe cytopathic changes, including higher interleukin-8 (IL-8) secretion, reduced cell viability, more pronounced “hummingbird phenotype” alterations, and increased cell migration and invasion compared to CagA W . Transcriptome analysis revealed that CagA E had a stronger effect on the up-regulation of key intracellular processes, including tumor necrosis factor-ɑ (TNF-ɑ) signal pathway via nuclear factor kappa-B (NF-κB), inflammatory response, interferon-γ (IFN-γ) response, hypoxia, ultraviolet (UV) response, and Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) signaling. A significant upregulation of hypoxia-related genes was a notable feature of CagA E . GES-1 cells infected with CagA E exhibited more severe intracellular hypoxia and higher levels of reactive oxygen species (ROS) than those infected with CagA W . Inhibition of hypoxia-inducible factor-1α (HIF-1α), which blocks hypoxia signaling, mitigated CagA E -induced cell migration, emphasizing the role of hypoxia in mediating CagA E effects. The study provides transcriptome evidence of CagA-associated intracellular regulation during H. pylori infection, demonstrating that CagA E exerts stronger effects on intracellular signaling than CagA W . These findings offer insights into the heightened carcinogenic potential of CagA E in H. pylori -induced gastric cancer.

Source: BMC Microbiology

DOI: 10.1186/s12866-024-03619-4