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  • Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis

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Helicobacter pylori
Original article
Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis
  1. Johanna C Sierra1,
  2. Mohammad Asim1,
  3. Thomas G Verriere1,
  4. M Blanca Piazuelo1,
  5. Giovanni Suarez1,
  6. Judith Romero-Gallo1,
  7. Alberto G Delgado1,
  8. Lydia E Wroblewski1,
  9. Daniel P Barry1,
  10. Richard M Peek Jr1,2,3,
  11. Alain P Gobert1,4,
  12. Keith T Wilson1,2,3,4,5
  1. 1Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  2. 2Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  3. 3Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  4. 4Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  5. 5Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
  1. Correspondence to Dr Keith T Wilson, Vanderbilt University Medical Center, 2215 Garland Ave, MRB IV 1030C, Nashville, TN 37232, USA; keith.wilson{at}vanderbilt.edu

Abstract

Objective Gastric cancer is the third leading cause of cancer death worldwide and infection by Helicobacter pylori is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the H. pylori-induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis.

Design We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of H. pylori-induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of Egfr (EfgrΔepi mice) were also used.

Results In C57BL/6 mice, gefitinib decreased Cxcl1 and Cxcl2 expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by H. pylori infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected EgfrΔepi versus Egfrfl/fl control mice. In H. pylori-infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked H. pylori-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from EfgrΔepi versus Egfrfl/fl mice. Epithelial EGFR activation persisted in humans and mice after H. pylori eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics.

Conclusions These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in H. pylori-infected individuals.

  • HELICOBACTER PYLORI
  • GASTRIC CANCER
  • CHEMOKINES
  • CHEMOPREVENTION
  • EPIDERMAL GROWTH FACTOR

https://doi.org/10.1136/gutjnl-2016-312888

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    Footnotes

    • Correction notice This article has been corrected since it published Online First. Figure 9 has been amended.

    • Contributors JCS performed the experiments, analysed the data and drafted the manuscript. MA, TGV, GS, JR-G, AGD and LEW performed experiments. MBP analysed and scored all of the tissue sections. DPB designed and generated epithelial-specific knockout mice. RMP provided funding and commented on the manuscript. APG designed experiments and revised the manuscript. KTW designed the experiments, analysed the data, supervised the studies, obtained funding and also wrote the paper.

    • Funding This study was funded by National Institutes of Health (NIH) grants R01DK053620, R01AT004821, R01CA190612 and P01CA028842 (to KTW), and P01CA116087 (to KTW and RMP), a Department of Veterans Affairs Merit Review grant I01BX001453 (to KTW), the Thomas F. Frist Sr. Endowment (to KTW), the Vanderbilt Center for Mucosal Inflammation and Cancer (to KTW and APG), the Vanderbilt Digestive Disease Research Center, funded by NIH grant P30DK058404 and the Vanderbilt Ingram Cancer Center, funded by NIH grant P30CA068485.

    • Competing interests None declared.

    • Ethics approval All animal study protocols were approved by the Vanderbilt University Institutional Animal Care and Use Committee.

    • Provenance and peer review Not commissioned, externally peer reviewed.