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Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells
Open accessAbstract
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.
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“Organoids infected with HRV or rotavirus enterotoxin showed lumenal swelling, a characteristic of rotavirus-induced diarrhea181.”
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Metadata
- Authors
- Wroblewski, L. E., Piazuelo, M. B., Chaturvedi, R., Schumacher, M., Aihara, E., Feng, R., Noto, J. M., Delgado, A., Israel, D. A., Zavros, Y., Montrose, M. H., Shroyer, N., Correa, P., Wilson, K. T., & Peek, R. M.
- Affiliations
- Vanderbilt University (US)
- University of Cincinnati (US)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Peek, Richard M
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2014-08-14
- Volume
- 64
- Issue
- 5
- Pages
- 720-730
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC4329117
- OpenAlex
- W2164422245
- Cited by
- 143
- References
- 53
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 4 · 2023: 13 · 2022: 16 · 2021: 19 · 2020: 14 · 2019: 12 · 2018: 10 · 2017: 16 · 2016: 18 · 2015: 11 · 2014: 1
- FWCI
- 15.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX001453)
- National Institutes of Health (1k01at007324-01, CA 116087, CA-77955, DK 058404)
- National Cancer Institute (CA028842, CA116087), R29CA077955, P01CA028842, CA-77955, R01CA190612, CA 153539, F32CA153539, R01CA077955, P01CA116087)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK058404, R01DK058587, R01DK054940, R01DK083402, R01DK053620, DK-58587, DK053620, R01DK073902, P30DK058404, P30DK078392)
- National Center for Complementary and Integrative Health (K01-AT-007324, R01AT004821, AT 007324)
- Topics
- Health Sciences › Medicine › Gastroenterology › Helicobacter pylori-related gastroenterology studies
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Oncology › Gastric Cancer Management and Outcomes
- Keywords
- Helicobacter pylori, claudin-7, gastric epithelial cells, MKN28 cells, β-catenin, snails, tight junctions, apical junctions, epithelial cell proliferation, gastric cancer risk, host-pathogen interaction
- MeSH terms
- Snail Family Transcription Factors, Animals, Cells, Cultured, Epithelial Cells, Gastric Mucosa, Humans, Mice, Inbred C57BL, Transcription Factors, Helicobacter pylori, Helicobacter Infections, Coculture Techniques, Cell Proliferation, beta Catenin, Claudins
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