Helicobacter Pylori-Induced DNA Double-Strand Breaks and Gastric Cancer
Abstract
Helicobacter pylori is the causative agent of gastric cancer. H. pylori infection induces DNA double-strand breaks (DSBs) in gastric epithelial cells and compromises their genomic integrity. While the genotoxicity of H. pylori promotes gastric carcinogenesis, the underlying molecular mechanisms are not fully understood. Here we show that H. pylori induces DNA DSBs in human gastric adenocarcinoma (AGS) cells through NF-B activation. Inhibition of NF-B in AGS cells by the expression of N-IB, a degradation-resistant mutant of IB (inhibitor of NF-B), dramatically reduces H. pylori-induced DNA DSBs. Further, type IV secretion system (T4SS)-dependent injection of H. pylori cytotoxin associated gene A (CagA) into AGS cells promotes NF-B activation and accumulation of a nucleic acid structure known as an R-loop, leading to DNA DSBs. Analyses of CagA mutants indicated that tyrosine phosphorylation of the EPIYA motifs is critical and a CagA mutant, ABTCCC, containing three copies of the EPIYA motif was more potent than wild-type CagA (ABC) in activating NF-B and inducing DNA DSBs, but not more carcinogenic. Our results suggest that NF-B and R-loop-driven genomic instability caused by CagA underlies the tumorigenic effect of H.pylori. As the oncogenicity of the ABTCCC strains is not significantly increased, other activities of CagA or other H. pylori virulence factors likely also play a role.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2022
- Accession Number
- AD1199730
Entities
People
- Douglas S. Merrell
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine