| Abstract: | The cytotoxin-associated gene (Cag) pathogenicity island is a strain-specificconstituent of Helicobacter pylori (H. pylori) thataugments cancer risk. CagA translocates into the cytoplasm where it stimulates cellsignaling through the interaction with tyrosine kinase c-Met receptor, leadingcellular proliferation. Identified as a potential gastric stem cell marker,cluster-of-differentiation (CD) CD44 also acts as a co-receptor for c-Met, butwhether it plays a functional role in H. pylori-induced epithelialproliferation is unknown. We tested the hypothesis that CD44 plays a functional rolein H. pylori-induced epithelial cell proliferation. To assay changesin gastric epithelial cell proliferation in relation to the direct interaction withH. pylori, human- and mouse-derived gastric organoids wereinfected with the G27 H. pylori strain or a mutant G27 strainbearing cagA deletion (∆CagA::cat). Epithelial proliferationwas quantified by EdU immunostaining. Phosphorylation of c-Met was analyzed byimmunoprecipitation followed by Western blot analysis for expression of CD44 andCagA. H. pylori infection of both mouse- and human-derived gastricorganoids induced epithelial proliferation that correlated with c-Metphosphorylation. CagA and CD44 co-immunoprecipitated with phosphorylated c-Met. Theformation of this complex did not occur in organoids infected with∆CagA::cat. Epithelial proliferation in response toH. pylori infection was lost in infected organoids derived fromCD44-deficient mouse stomachs. Human-derived fundic gastric organoids exhibited aninduction in proliferation when infected with H. pylorithat was notseen in organoids pre-treated with a peptide inhibitor specific to CD44. In thewell-established Mongolian gerbil model of gastric cancer, animals treated with CD44peptide inhibitor Pep1, resulted in the inhibition of H.pylori-induced proliferation and associated atrophic gastritis. The currentstudy reports a unique approach to study H. pylori interaction withthe human gastric epithelium. Here, we show that CD44 plays a functional role inH. pylori-induced epithelial cell proliferation. |
