Abstract
Epstein-Barr virus (EBV)-associated gastric cancer belongs to 1 of the 4 subtypes of gastric cancer and accounts for 10% of total gastric cancers. However, most cases of gastric cancer have a history of Helicobacter pylori infection. Therefore, we investigated the possibility that H. pylori infection promotes the development of EBV-associated gastric cancer. H. pylori was exposed to principal EBV receptor, CD21, negative gastric epithelial cells, and then infected with EBV recombinant expressing enhanced green fluorescent protein. Changes in EBV infectivity due to prior H. pylori exposure were analyzed using flow cytometry. The treatment of gastric epithelial cells with H. pylori increased the efficiency of EBV infection. An increase was also observed when CagA-deficient, VacA-deficient, and FlaA-deficient H. pylori strains were used, but not when cag pathogenicity island-deficient H. pylori was used. The treatment of epithelial cells with H. pylori induced the expression of accessory EBV receptors, EphA2 and NMHC-IIA, and increased the efficiency of EBV infection depending on their expression levels. When gastric epithelial cells were treated with EPHA2 or NMHC-IIA siRNA, EBV infection via H. pylori attachment was decreased. The adhesion of H. pylori induced the expression of accessory EBV receptors in gastric epithelial cells and increased the efficiency of EBV infection.
Keywords:
Helicobacter pylori; Epstein-Barr virus; bacterial-viral association; ephrin type-A receptor 2; gastric cancer; non-muscle myosin heavy chain IIA.
© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
MeSH terms
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Antigens, Bacterial / metabolism
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Attachment Sites, Microbiological / physiology
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Bacterial Adhesion / physiology
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Bacterial Proteins / metabolism
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Cell Line, Tumor
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Epithelial Cells / drug effects
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Epithelial Cells / microbiology
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Epstein-Barr Virus Infections / etiology*
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Green Fluorescent Proteins / metabolism
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Helicobacter Infections / complications*
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Helicobacter Infections / metabolism
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Helicobacter pylori / drug effects
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Helicobacter pylori / genetics
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Helicobacter pylori / physiology*
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Herpesvirus 4, Human* / metabolism
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Herpesvirus 4, Human* / pathogenicity
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Humans
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Hydro-Lyases / deficiency
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Myosin Heavy Chains / genetics
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Myosin Heavy Chains / metabolism
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Oxidoreductases / deficiency
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RNA, Small Interfering / pharmacology
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Receptor, EphA2 / genetics
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Receptor, EphA2 / metabolism
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Receptors, Complement 3d / metabolism
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Stomach Neoplasms / microbiology
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Stomach Neoplasms / virology*
Substances
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Antigens, Bacterial
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Bacterial Proteins
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FlaA1 protein, Helicobacter pylori
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RNA, Small Interfering
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Receptors, Complement 3d
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VacA protein, Helicobacter pylori
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cagA protein, Helicobacter pylori
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Green Fluorescent Proteins
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Oxidoreductases
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Receptor, EphA2
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Myosin Heavy Chains
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Hydro-Lyases
Grants and funding
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20fk0310105h0004/Japan Agency for Medical Research and Development (AMED)
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18K07147/Ministry of Education, Culture, Sports, Science and Technology in Japan
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18K07148/Ministry of Education, Culture, Sports, Science and Technology in Japan
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18K15168/Ministry of Education, Culture, Sports, Science and Technology in Japan
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20K07479/Ministry of Education, Culture, Sports, Science and Technology in Japan
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20K09712/Ministry of Education, Culture, Sports, Science and Technology in Japan
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FY2020 Shimane University Internal Competitive Grants
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The Otsuka Toshimi Scholarship Foundation
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the Kobayashi Foundation
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the Program of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science