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PLoS Pathog. 2015 Feb 6;11(2):e1004663. doi: 10.1371/journal.ppat.1004663. eCollection 2015 Feb.

CD44 plays a functional role in Helicobacter pylori-induced epithelial cell proliferation.

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Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
Department of Surgery, Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
Department of Microbiology and Environmental Toxicology, University of California at Santa Cruz, Santa Cruz, California, United States of America.
Karlsruhe Institute of Technology, Institute for Toxicology and Genetics, Hermann von Helmholtzplatz, Germany.
Department of Pathology Wright State University, Health Sciences, Dayton, Ohio, United States of America; Veterans Affairs Medical Center, Cincinnati, Ohio, United States of America.


The cytotoxin-associated gene (Cag) pathogenicity island is a strain-specific constituent of Helicobacter pylori (H. pylori) that augments cancer risk. CagA translocates into the cytoplasm where it stimulates cell signaling through the interaction with tyrosine kinase c-Met receptor, leading cellular proliferation. Identified as a potential gastric stem cell marker, cluster-of-differentiation (CD) CD44 also acts as a co-receptor for c-Met, but whether it plays a functional role in H. pylori-induced epithelial proliferation is unknown. We tested the hypothesis that CD44 plays a functional role in H. pylori-induced epithelial cell proliferation. To assay changes in gastric epithelial cell proliferation in relation to the direct interaction with H. pylori, human- and mouse-derived gastric organoids were infected with the G27 H. pylori strain or a mutant G27 strain bearing cagA deletion (∆CagA::cat). Epithelial proliferation was quantified by EdU immunostaining. Phosphorylation of c-Met was analyzed by immunoprecipitation followed by Western blot analysis for expression of CD44 and CagA. H. pylori infection of both mouse- and human-derived gastric organoids induced epithelial proliferation that correlated with c-Met phosphorylation. CagA and CD44 co-immunoprecipitated with phosphorylated c-Met. The formation of this complex did not occur in organoids infected with ∆CagA::cat. Epithelial proliferation in response to H. pylori infection was lost in infected organoids derived from CD44-deficient mouse stomachs. Human-derived fundic gastric organoids exhibited an induction in proliferation when infected with H. pylori that was not seen in organoids pre-treated with a peptide inhibitor specific to CD44. In the well-established Mongolian gerbil model of gastric cancer, animals treated with CD44 peptide inhibitor Pep1, resulted in the inhibition of H. pylori-induced proliferation and associated atrophic gastritis. The current study reports a unique approach to study H. pylori interaction with the human gastric epithelium. Here, we show that CD44 plays a functional role in H. pylori-induced epithelial cell proliferation.

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