Abstract
Downregulation of HLA class I expression may contribute to a poor prognosis in cancer patients. There is limited information about epigenetic and oncogenic regulation of HLA class I, and multiple mechanisms may be involved. In the current study, we examined the relationship between the HER2-signaling pathway (MAPK and PI3K-Akt) and the expression of HLA class I and Ag-processing machinery (APM) components. A panel of gastric and esophageal cancer cell lines was treated with wortmannin as an Akt-signal inhibitor; the MAPK signal inhibitor PD98059; lapatinib, which inhibits both the epidermal growth factor receptor and HER2 tyrosine kinase; or siRNA for MAPK. The levels of HER2-signaling molecules, APM components, and HLA class I were evaluated by Western blot, quantitative PCR, and flow cytometry. Resected gastric tumor tissues (n = 102) were analyzed for p-Erk and HLA class I expression by immunohistochemistry. As a result, inhibition of the MAPK pathway induced upregulation of HLA-A02 and HLA-A24 expression in parallel with an increase in APM components and enhanced target sensitivity to tumor Ag-specific CTL lysis. HLA-A expression was predominantly regulated by the MAPK pathway, but it was also influenced, in part, by the Akt pathway. There was a strong inverse correlation between p-Erk expression and HLA class I expression in clinical tumor samples. In conclusion, HLA-A expression is predominantly regulated by the MAPK pathway in gastric and esophageal cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Antigen Presentation / genetics
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Antigens, Neoplasm / biosynthesis*
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Antigens, Neoplasm / genetics
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Cell Line, Tumor
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / antagonists & inhibitors
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Esophageal Neoplasms / genetics
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Esophageal Neoplasms / immunology*
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Esophageal Neoplasms / pathology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Flavonoids / pharmacology
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Gene Expression Regulation, Neoplastic / physiology*
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Genes, MHC Class I
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HLA-A Antigens / biosynthesis*
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HLA-A Antigens / genetics
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Humans
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Lapatinib
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / physiology
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Protein Processing, Post-Translational / drug effects
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / physiology
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Quinazolines / pharmacology
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RNA, Small Interfering / pharmacology
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Receptor, ErbB-2 / antagonists & inhibitors
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Stomach Neoplasms / genetics
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Stomach Neoplasms / immunology*
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Stomach Neoplasms / pathology
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Wortmannin
Substances
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Androstadienes
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Antigens, Neoplasm
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Flavonoids
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HLA-A Antigens
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Quinazolines
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RNA, Small Interfering
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Lapatinib
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Epidermal Growth Factor
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EGFR protein, human
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ERBB2 protein, human
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ErbB Receptors
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Receptor, ErbB-2
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Wortmannin