Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells

Lydia E. Wroblewski, M. Blanca Piazuelo, Rupesh Chaturvedi, Michael Schumacher, Eitaro Aihara, Rui Feng, Jennifer M. Noto, Alberto Delgado, Dawn A. Israel, Yana Zavros, Marshall H. Montrose, Noah Shroyer, Pelayo Correa, Keith T. Wilson, Richard M. Peek

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Objective Helicobacter pylori strains that express the oncoprotein CagA augment risk for gastric cancer. However, the precise mechanisms through which cag+ strains heighten cancer risk have not been fully delineated and model systems that recapitulate the gastric niche are critical for understanding pathogenesis. Gastroids are three-dimensional organ-like structures that provide unique opportunities to study host-H. pylori interactions in a preclinical model. We used gastroids to inform and direct in vitro studies to define mechanisms through which H. pylori modulates expression of the cancer-associated tight junction protein claudin-7. Design Gastroids were infected by luminal microinjection, and MKN28 gastric epithelial cells were cocultured with H. pylori wild-type cag+ strains or isogenic mutants. β-catenin, claudin-7 and snail localisation was determined by immunocytochemistry. Proliferation was assessed using 5-ethynyl-20-deoxyuridine, and levels of claudin-7 and snail were determined by western blot and flow cytometry. Results Gastroids developed into a self-organising differentiation axis and H. pylori induced mislocalisation of claudin-7 and increased proliferation in a CagA-and β-catenin-dependent manner. In MKN28 cells, H pyloriinduced suppression of claudin-7 was regulated by β-catenin and snail. Similarly, snail expression was increased and claudin-7 levels were decreased among H. pylori-infected individuals. Conclusions H. pylori increase proliferation in a strainspecific manner in a novel gastroid system. H. pylori also alter expression and localisation of claudin-7 in gastroids and human epithelial cells, which is mediated by β-catenin and snail activation. These data provide new insights into molecular interactions with carcinogenic potential that occur between H. pylori and epithelial cells within the gastric niche.

Original languageEnglish (US)
Pages (from-to)720-730
Number of pages11
JournalGut
Volume64
Issue number5
DOIs
StatePublished - Apr 9 2015
Externally publishedYes

ASJC Scopus subject areas

  • Gastroenterology

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