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Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells
  1. Lydia E Wroblewski1,
  2. M Blanca Piazuelo1,
  3. Rupesh Chaturvedi1,
  4. Michael Schumacher2,
  5. Eitaro Aihara2,
  6. Rui Feng2,
  7. Jennifer M Noto1,
  8. Alberto Delgado1,
  9. Dawn A Israel1,
  10. Yana Zavros2,
  11. Marshall H Montrose2,
  12. Noah Shroyer3,
  13. Pelayo Correa1,
  14. Keith T Wilson1,
  15. Richard M Peek Jr1
  1. 1Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  2. 2Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, USA
  3. 3Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital, Cincinnati, Ohio, USA
  1. Correspondence to Dr Richard M Peek Jr, Division of Gastroenterology, Vanderbilt University School of Medicine, 2215 Garland Ave., 1030C MRB IV, Nashville, TN 37232-2279, USA; richard.peek{at}vanderbilt.edu

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-2′-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 pylori-induced 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 strain-specific 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.

  • HELICOBACTER PYLORI
  • GASTRIC CANCER
  • CELL PROLIFERATION
  • TIGHT JUNCTION
  • GASTRIC INFLAMMATION

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