More powerful dysregulation of Helicobacter pylori East Asian-type CagA on intracellular signalings
Xiaofei Ji, Zekun Sun, Hao Wu, Jianhui Zhang, Shuzhen Liu, Xinying Cao, Bin Wang, Feifan Wang, Ying Zhang, Boqing Li, Jiankai Feng, Huilin Zhao
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.