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Helicobacter pylori Cytotoxin-Associated Gene A Activates the Signal Transducer and Activator of Transcription 3 Pathway In vitro and In vivo
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Abstract
Persistent infection with Helicobacter pylori confers an increased risk for the development of gastric cancer. However, the exact mechanisms whereby this bacterium causes carcinogenesis have not been completely elucidated. Recent evidence indicates that aberrant activation of the signal transducers and activators of transcription 3 (STAT3) signaling pathway may play a role in gastric carcinogenesis. Therefore, we hypothesized that H. pylori infection modulates STAT3 signaling, favoring gastric cancer development. In epithelial cells infected with H. pylori, STAT3 was activated, as assessed by immunoblotting for phosphorylated STAT3, immunofluorescence of translocated STAT3, fluorescence recovery after photobleaching, and luciferase activation in transfected cells. Activation was dependent on translocation but not phosphorylation of cytotoxin-associated gene A (CagA) in host cells. Activation seemed to be receptor-mediated because preincubation of cells with the interleukin-6 (IL-6) receptor superantagonist sant7 or inhibition of gp130 by a monoclonal antibody prevented H. pylori–mediated STAT3 activation. However, activation was not related to autocrine activation by IL-6 or IL-11. CagA+ wild-type H. pylori, but not the noncarcinogenic cagA− mutant, activated STAT3 in gastric epithelial cells in vivo in the gerbil model of H. pylori–mediated gastric carcinogenesis. Collectively, these results indicate that H. pylori CagA activates the STAT3 signaling pathway in vitro and in vivo, providing a potential mechanism by which chronic H. pylori infection promotes the development of gastric cancer. [Cancer Res 2009;69(2):632–9]
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“Helicobacter pylori, which induces gastritis and is related to gastric cancer, activates STAT3 in epithelial cells (327).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [327]
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Metadata
- Authors
- Bronte-Tinkew, D. M., Terebiznik, M., Franco, A., Ang, M., Ahn, D., Mimuro, H., Sasakawa, C., Ropeleski, M. J., Peek, R. M., & Jones, N. L.
- Affiliations
- University of Toronto (CA)
- Vanderbilt University (US)
- Institute of Medical Science, The University of Tokyo (JP)
- Queen's University (CA)
- ORCID
- Venue
- Cancer Research
- Published
- 2009-01-15
- Volume
- 69
- Issue
- 2
- Pages
- 632-639
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3418672
- OpenAlex
- W2117113786
- Cited by
- 154
- References
- 33
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 8 · 2023: 14 · 2022: 7 · 2021: 6 · 2020: 10 · 2019: 5 · 2018: 6 · 2017: 8 · 2016: 11 · 2015: 8 · 2014: 11 · 2013: 13 · 2012: 13
- FWCI
- 10.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R29CA077955, CA-77955, R01CA077955)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-73902, R01DK058587, DK-58587, R01DK073902)
- Topics
- Health Sciences › Medicine › Gastroenterology › Helicobacter pylori-related gastroenterology studies
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Oncology › Gastric Cancer Management and Outcomes
- Keywords
- Helicobacter pylori, CagA, cytotoxin-associated gene A, STAT3 signaling, gastric carcinogenesis, gp130, IL-6 receptor, interleukin-11, chronic infection, gastric epithelial cells, gerbil model
- MeSH terms
- Adenocarcinoma, Animals, Antigens, Bacterial, Bacterial Proteins, Cell Nucleus, Gerbillinae, HeLa Cells, Humans, Male, Phosphorylation, Stomach Neoplasms, Transcription, Genetic, Tyrosine, Helicobacter pylori, Helicobacter Infections, Receptors, Interleukin-6, Cell Line, Tumor, STAT3 Transcription Factor, Cytokine Receptor gp130
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