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Gut. 2015 May;64(5):720-30. doi: 10.1136/gutjnl-2014-307650. Epub 2014 Aug 14.

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

Author information

1
Division of Gastroenterology, Departments of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
2
Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, USA.
3
Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.

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.

KEYWORDS:

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

PMID:
25123931
PMCID:
PMC4329117
DOI:
10.1136/gutjnl-2014-307650
[Indexed for MEDLINE]
Free PMC Article

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