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

• Published in: BMC microbiology Vol. 24; no. 1; pp. 467 - 15
• Main Authors: Ji, Xiaofei, Sun, Zekun, Wu, Hao, Zhang, Jianhui, Liu, Shuzhen, Cao, Xinying, Wang, Bin, Wang, Feifan, Zhang, Ying, Li, Boqing, Feng, Jiankai, Zhao, Huilin
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.11.2024; BioMed Central; BMC
• Subjects: Analysis; Antigens, Bacterial - genetics; Antigens, Bacterial - metabolism; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biotechnology; CagA; Cancer; Carcinogens; Care and treatment; Cell culture; Cell Line; Cell migration; Cell Movement; Cell viability; Chronic infection; Complications and side effects; Diagnosis; E coli; East Asian People; Epithelial cells; Epithelial Cells - microbiology; Epithelium; Gastric cancer; Gastric Mucosa - microbiology; Gastric Mucosa - pathology; Gastrointestinal diseases; Gene expression; Growth factors; Helicobacter infections; Helicobacter Infections - microbiology; Helicobacter pylori; Helicobacter pylori - genetics; Helicobacter pylori - pathogenicity; Humans; Hypoxia; Hypoxia-inducible factor 1a; Infections; Inflammation; Inflammatory response; Interleukin 8; Interleukin-8 - genetics; Interleukin-8 - metabolism; Intracellular; Intracellular signalling; Kinases; Laboratory animals; NF-κB protein; Phenotypes; Plasmids; Reactive oxygen species; Risk factors; Sarcoma; Signal Transduction; Stomach Neoplasms - genetics; Stomach Neoplasms - microbiology; Transcriptome analysis; Transcriptomes; Up-regulation; Virulence (Microbiology); γ-Interferon; China; United Kingdom > UK; United States > US; Hypoxia; Transcriptome analysis; Helicobacter pylori; Gastric cancer; CagA
• ISSN: 1471-2180; 1471-2180
• DOI: 10.1186/s12866-024-03619-4

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 and CagA ), with CagA being more closely associated with gastric cancer. This study aimed to investigate the impact of CagA on intracellular signaling pathways to explain its high oncogenicity. Mutant H. pylori strains expressing either CagA or CagA were generated by transforming CagA -expression plasmid into CagA-deleted G27 strain (G27 ). In human gastric epithelial cells (GES-1) infection, CagA 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 . Transcriptome analysis revealed that CagA 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 . GES-1 cells infected with CagA exhibited more severe intracellular hypoxia and higher levels of reactive oxygen species (ROS) than those infected with CagA . Inhibition of hypoxia-inducible factor-1α (HIF-1α), which blocks hypoxia signaling, mitigated CagA -induced cell migration, emphasizing the role of hypoxia in mediating CagA effects. The study provides transcriptome evidence of CagA-associated intracellular regulation during H. pylori infection, demonstrating that CagA exerts stronger effects on intracellular signaling than CagA . These findings offer insights into the heightened carcinogenic potential of CagA in H. pylori-induced gastric cancer.