Abstract
Autoimmune regulator (AIRE) is a transcriptional regulator that is primarily expressed in medullary epithelial cells, where it induces tissue-specific antigen expression. Under pathological conditions, AIRE expression is induced in epidermal cells and promotes skin tumor development. This study aimed to clarify the role of AIRE in the pathogenesis of oral squamous cell carcinoma (OSCC). AIRE expression was evaluated in six OSCC cell lines and in OSCC tissue specimens. Expression of STAT1, ICAM1, CXCL10, CXCL11, and MMP9 was elevated in 293A cells stably expressing AIRE, and conversely, was decreased in AIRE-knockout HSC3 OSCC cells when compared to the respective controls. Upregulation of STAT1, and ICAM in OSCC cells was confirmed in tissue specimens by immunohistochemistry. We provide evidence that AIRE exerts transcriptional control in cooperation with ETS1. Expression of STAT1, ICAM1, CXCL10, CXCL11, and MMP9 was increased in 293A cells upon Ets1 transfection, and coexpression of AIRE further increased the expression of these proteins. AIRE coprecipitated with ETS1 in a modified immunoprecipitation assay using formaldehyde crosslinking. Chromatin immunoprecipitation and quantitative PCR analysis revealed that promoter fragments of STAT1, ICAM1, CXCL10, and MMP9 were enriched in the AIRE precipitates. These results indicate that AIRE is induced in OSCC and supports cancer-related gene expression in cooperation with ETS1. This is a novel function of AIRE in extrathymic tissues under the pathological condition.
Highlights
The burden of oral cancer has significantly increased in many parts of the world, causing more than 145.000 death in 2012 worldwide [1]
Autoimmune regulator (AIRE)-positive cells were positive for keratin 14 (KRT14), confirming that they were medullary thymic epithelial cells (mTECs)
Twenty-seven cases showed a distinctive increase (“++”), 20 cases showed a weak increase (“+”), and four cases showed unremarkable change (“+/–”) in AIRE expression. These results indicated that AIRE expression is significantly increased in oral squamous cell carcinoma (OSCC) compared to normal epithelium (Fig 2E)
Summary
The burden of oral cancer has significantly increased in many parts of the world, causing more than 145.000 death in 2012 worldwide [1]. Under the influence of interaction with the tumor microenvironment, cancer cells express a unique group of proteins that are absent or expressed at very low levels in normal cells. Expressed proteins in OSCC compared to normal keratinocytes include various cytokines, chemokines (for example, CXCLs), extracellular matrix proteins, matrix remodeling enzymes (for example, matrix metalloproteases (MMPs)), cell adhesion molecules, and cytoskeletal proteins [3,4]. Among these factors that characterize cancer cells, we have been interested in keratin 17 (KRT17) because it is consistently and strongly induced in OSCC, and because of its unique functions. AIRE was first identified as a causative gene for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome, which gives rise to multiple endocrine disorders, chronic mucocutaneous candidiasis, and various ectodermal defects
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