H-pylori CagL-Y58/E59 Prime Higher Integrin α5β1 in Adverse pH Condition to Enhance Hypochlorhydria Vicious Cycle for Gastric Carcinogenesis

Background/Aims: H. pylori CagL amino acid polymorphisms such as Y58/E59 can increase integrin alpha 5 beta 1 expression and gastric cancer risk. Hypochlorhydria during chronic H. pylori infection promotes gastric carcinogenesis. The study test whether CagL-Y58/E59 isolates may regulate integrin alpha 5 beta 1 to translocate CagA via the type IV secretory system even under adverse pH conditions, and whether the integrin alpha 5 beta 1 expression primed by H. pylori is a pH-dependent process involving hypochlorhydria in a vicious cycle to promote gastric carcinogenesis. Methods: The expressions of integrin alpha 5 and beta 1, CagA phosphorylation, IL-8, FAK, EGFR, and AKT activation of AGS cells exposed to CagL-Y58/E59 H. pylori, isogenic mutants, and different H. pylori CagL amino acid replacement mutants under different pH values were determined. Differences in the pepsinogen I/II ratio (indirectly indicating gastric acidity) and gastric integrin alpha 5 beta 1 expression were compared among the 172 H. pylori-infected patients with different cancer risks. Results: Even under adversely low pH condition, H. pylori CagL-Y58/E59 still keep active integrin beta 1 with stronger binding affinity, CagA translocation, IL-8, FAK, EGFR, and AKT activation than the other mutants (p<0.05). The in vitro assay revealed higher priming of integrin alpha 5 beta 1 by H. pylori under elevated pH as hypochlorhydria (p<0.05). In the H. pylori-infected patients, the gastric integrin alpha 5 beta 1 expressions were higher in those with pepsinogen I/II ratio,6 than in those without (p<0.05). Conclusions: H. pylori CagL-Y58/E59 prime higher integrin under adverse pH and may involve to enhance hypochlorhydria vicious cycle for gastric carcinogenesis, and thus require an early eradication.