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

Abstract

Background: 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.

Results: 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.

Conclusions: 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.