title: CD44 plays a functional role in Helicobacter pylori-induced epithelial cell proliferation.
abstract: 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.
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Nina
authors: N
authors: Bertaux-Skeirik
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Rui
authors: R
authors: Feng
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Michael A
authors: MA
authors: Schumacher
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Jing
authors: J
authors: Li
authors: Department of Surgery, Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors: Maxime M
authors: MM
authors: Mahe
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Amy C
authors: AC
authors: Engevik
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Jose E
authors: JE
authors: Javier
authors: Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Richard M
authors: RM
authors: Peek
authors: Department of Microbiology and Environmental Toxicology, University of California at Santa Cruz, Santa Cruz, California, United States of America.
authors: Karen
authors: K
authors: Ottemann
authors: Karlsruhe Institute of Technology, Institute for Toxicology and Genetics, Hermann von Helmholtzplatz, Germany.
authors: Veronique
authors: V
authors: Orian-Rousseau
authors: Department of Pathology Wright State University, Health Sciences, Dayton, Ohio, United States of America; Veterans Affairs Medical Center, Cincinnati, Ohio, United States of America.
authors: Gregory P
authors: GP
authors: Boivin
authors: Department of Surgery, Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors: Michael A
authors: MA
authors: Helmrath
authors: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Yana
authors: Y
authors: Zavros
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology* / Q000473:pathology; D005748:Gastric Fundus / Q000276:immunology / Q000382:microbiology; D005753:Gastric Mucosa / Q000276:immunology* / Q000382:microbiology; D017353:Gene Deletion; D016481:Helicobacter Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D051379:Mice; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C080866:cagA protein, Helicobacter pylori; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases