Reference - Detail
|Author||Mimura K, Shiraishi K, Mueller A, Izawa S, Kua LF, So J, Yong WP, Fujii H, Seliger B, Kiessling R, Kono K.|
|Title||The MAPK pathway is a predominant regulator of HLA-A expression in esophageal and gastric cancer.|
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.
|MeSH||Androstadienes / pharmacology Antigen Presentation / genetics Antigens, Neoplasm / biosynthesis* Antigens, Neoplasm / genetics Cell Line, Tumor Epidermal Growth Factor / pharmacology ErbB Receptors / antagonists & inhibitors Esophageal Neoplasms / genetics Esophageal Neoplasms / immunology* Esophageal Neoplasms / pathology Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors Flavonoids / pharmacology Gene Expression Regulation, Neoplastic / physiology* Genes, MHC Class I HLA-A Antigens / biosynthesis* HLA-A Antigens / genetics Humans Lapatinib MAP Kinase Signaling System / drug effects MAP Kinase Signaling System / physiology* Neoplasm Proteins / antagonists & inhibitors Neoplasm Proteins / physiology Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology Protein Processing, Post-Translational / drug effects Proto-Oncogene Proteins c-akt / antagonists & inhibitors Proto-Oncogene Proteins c-akt / physiology Quinazolines / pharmacology RNA, Small Interfering / pharmacology Receptor, ErbB-2 / antagonists & inhibitors Signal Transduction / drug effects Signal Transduction / physiology Stomach Neoplasms / genetics Stomach Neoplasms / immunology* Stomach Neoplasms / pathology Wortmannin|
|Human and Animal Cells|