Year: 2015
Type: article
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.
Source: PLoS Pathogens
Language: English
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: Cincinnati Children's Hospital Medical Center, University of Cincinnati, American Gastroenterological Association, National Institutes of Health, College of Medicine, University of Cincinnati, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
Awards: G1898739998, Helicobacter Pylori and Gastrointestinal Biology, Advanced Multidisciplinary Training Program for Systems Biology, G295821465, The role of Hedgehog Signaling in gastric tissue repair and regeneration, Center for Clinical and Translational Science and Training, G5659890370, G575058197, Cincinnati Rheumatic Disease Core Center, G9000082453, G9000276564, Molecular and Cellular Basis for Digestive Diseases, Digestive Health Center (DHC): Bench to Bedside Research in Pediatric Digestive Disease, H. pylori-induced Inflammation and Gastric Cancer, G953648728
OpenAlex ID: W2085844606