Keith Wilson
Faculty Member
Last active: 12/19/2020

Publication

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

Wroblewski LE, Piazuelo MB, Chaturvedi R, Schumacher M, Aihara E, Feng R, Noto JM, Delgado A, Israel DA, Zavros Y, Montrose MH, Shroyer N, Correa P, Wilson KT, Peek RM
Gut. 2015 64 (5): 720-30

PMID: 25123931 · PMCID: PMC4329117 · DOI:10.1136/gutjnl-2014-307650

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.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

MeSH Terms (14)

Animals beta Catenin Cell Proliferation Cells, Cultured Claudins Coculture Techniques Epithelial Cells Gastric Mucosa Helicobacter Infections Helicobacter pylori Humans Mice, Inbred C57BL Snail Family Transcription Factors Transcription Factors

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