Format

Send to

Choose Destination
See comment in PubMed Commons below
PLoS Pathog. 2015 Feb 6;11(2):e1004663. doi: 10.1371/journal.ppat.1004663. eCollection 2015.

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

Author information

1
Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
2
Department of Surgery, Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
3
Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
4
Department of Microbiology and Environmental Toxicology, University of California at Santa Cruz, Santa Cruz, California, United States of America.
5
Karlsruhe Institute of Technology, Institute for Toxicology and Genetics, Hermann von Helmholtzplatz, Germany.
6
Department of Pathology Wright State University, Health Sciences, Dayton, Ohio, United States of America; Veterans Affairs Medical Center, Cincinnati, Ohio, United States of America.

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.

PMID:
25658601
PMCID:
PMC4450086
DOI:
10.1371/journal.ppat.1004663
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Public Library of Science Icon for PubMed Central
    Loading ...
    Support Center