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.
Subject(s)
Carcinoma, Squamous Cell/genetics , Mouth Neoplasms/genetics , Transcription Factors/genetics , Transcriptional Activation , Autoimmunity , Cell Line, Tumor , Chromatin Immunoprecipitation , Gene Expression , HEK293 Cells , Humans , Promoter Regions, Genetic , Proto-Oncogene Protein c-ets-1/genetics , AIRE ProteinABSTRACT
Notch signaling functions in diverse developmental and homeostatic processes, including stem cell self-renewal and cell fate determination. Notch1-inactivating mutations are frequently detected in skin and oro-esophageal cancers, suggesting a role for Notch1 as a tumor suppressor. Here, we clarify the contribution of Notch1 deficiency to oro-esophageal tumorigenesis using a physiological experimental model. Tongue and esophageal tumors induced in mice by 4-nitroquinoline-1-oxide (4-NQO) showed pathophysiological similarities to human tumors, including decreased Notch1 expression in the basal cells. We created mutant mice (N1cKO), in which the Notch1 gene was disrupted specifically in the squamous epithelium. The epithelium formed normally in N1cKO mice, and although multiple skin tumors were detected at 65 weeks, no tumors developed in the tongue and esophagus. However, 4-NQO-induced tumorigenesis assays revealed that tumor onset occurred earlier in N1cKO mice than in wild-type littermates, and the tumors arose preferentially from the Notch1-negative epithelium, indicating the tumor susceptibility of Notch1-deficient epithelium. Notch1 regulates the expression of TERT, and age-related telomere erosion was more rapid in Notch1-deficient basal cells. Our results indicated that although Notch1 deficiency had little effect on squamous epithelium formation, it predisposed the affected epithelium to tumor development, at least in part through accelerated telomere erosion.
Subject(s)
Carcinogenesis/genetics , Esophageal Neoplasms/genetics , Receptor, Notch1/genetics , Tongue Neoplasms/genetics , 4-Nitroquinoline-1-oxide/toxicity , Animals , Disease Models, Animal , Epithelium/metabolism , Epithelium/pathology , Esophageal Neoplasms/chemically induced , Esophageal Neoplasms/pathology , Esophagus/metabolism , Esophagus/pathology , Gene Expression Regulation, Neoplastic/genetics , Humans , Mice , Mice, Knockout , Telomerase/genetics , Telomere/genetics , Tongue Neoplasms/chemically induced , Tongue Neoplasms/pathologyABSTRACT
NOTCH1 plays an important role in epithelial differentiation and carcinogenesis. To investigate the impact of Notch1 inactivation in oroesophageal epithelium, we generated conditional knockout (cKO) mice, using a combined construct which induces the expression of single guide RNA targeting Notch1 and Cas9 by the KRT14 promoter. The cKO mice exhibited patchy hair loss and multiple NOTCH1-negative areas in the tongue epithelium, indicative of heterogeneous knockout. The cKO mice showed susceptibility to esophageal tumorigenesis, underscoring Notch1 as a tumor suppressor. Our one-step strategy for generation of cKO mice provides a versatile method to examine a gene function in vivo.
Subject(s)
Carcinogenesis/metabolism , Disease Models, Animal , Esophageal Neoplasms/metabolism , Mice, Knockout/metabolism , Receptor, Notch1/metabolism , Animals , Carcinogenesis/pathology , Cell Line, Tumor , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Mice , Mice, Knockout/genetics , Mice, Knockout/immunology , Receptor, Notch1/geneticsABSTRACT
OBJECTIVE: To present a case of pyoderma gangrenosum (PG)-like oral ulcerations in an elderly patient. BACKGROUND: PG is an uncommon idiopathic, ulcerative, chronic inflammatory cutaneous disorder of unknown etiology, which is associated with systemic diseases found in more than 50% of patients. Oral lesions of PG are extremely rare and have not been previously reported on chronic leukemia patient. CLINICAL REPORT: This report presents the first case of a 73 year-old man who had PG-like oral ulcerations which offered the possibility of an initial finding of chronic myeloid leukemia. CONCLUSION: Clinicians should always take into consideration that PG in the oral mucosa is a recalcitrant ulcer and can precede the development of underlying clonal malignancy.
Subject(s)
Mouth Diseases/pathology , Mouth Mucosa/pathology , Oral Ulcer/pathology , Pyoderma Gangrenosum/pathology , Aged , Biopsy , Diagnosis, Differential , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Pyoderma Gangrenosum/diagnosis , Rare Diseases/diagnosis , ThailandABSTRACT
AIMS: Malignant odontogenic tumours (MOTs) are rare neoplasms occurring primarily within the jaw. The objective of this study was to determine the incidence, demographics and clinicopathological features of the MOTs from two institutions. METHODS AND RESULTS: The records of the Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand and the Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, USA were searched from 1991 to 2010; we identified 17 cases of previously diagnosed MOTs. All cases were reviewed independently of the previous diagnosis by two blinded oral pathologists and reclassified based on the 2005 World Health Organization classification of head and neck tumours. In this study we describe in detail these 17 cases which presented with an average age of 50.29 years and a male to female ratio of 2.4:1. These cases included five ameloblastic carcinomas, four atypical ameloblastomas, three primary intraosseous squamous cell carcinomas, three intraosseous mucoepidermoid carcinomas and two clear cell odontogenic carcinomas. All cases were treated by surgical resection and one patient with ameloblastic carcinoma received postoperative radiotherapy. CONCLUSIONS: Malignant odontogenic tumours are considered rare central odontogenic lesions. Awareness of their existence, rapid diagnosis and successful treatment using surgery, radiation and/or chemotherapy is critical to patient survival.
