Promotion of cell proliferation by the proto‐oncogene DEK enhances oral squamous cell carcinogenesis through field cancerization. (23rd August 2017)

• Record Type: Journal Article
• Authors: Nakashima, Takayuki; Tomita, Hiroyuki; Hirata, Akihiro; Ishida, Kazuhisa; Hisamatsu, Kenji; Hatano, Yuichiro; Kanayama, Tomohiro; Niwa, Ayumi; Noguchi, Kei; Kato, Keizo; Miyazaki, Tatsuhiko; Tanaka, Takuji; Shibata, Toshiyuki; Hara, Akira
• Is Part Of: Cancer medicine. Volume 6:Number 10(2017:Oct.)
• Page Start: 2424
• Page End: 2439
• Publication Date: 2017-08-23
• Subjects: DEK -- field cancerization -- oncogene -- squamous cell carcinoma; 616.994005
• DOI: 10.1002/cam4.1157
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: Oral squamous cell carcinoma (OSCC) develops through a multistep carcinogenic process involving field cancerization. The DEK gene is a proto‐oncogene with functions in genetic and epigenetic modifications, and has oncogenic functions, including cellular proliferation, differentiation, and senescence. DEK overexpression is associated with malignancies; however, the functional roles of DEK overexpression are unclear. We demonstrated that DEK ‐expressing cells were significantly increased in human dysplasia/carcinoma in situ and OSCC. Furthermore, we generated ubiquitous and squamous cell‐specific doxycycline (DOX)‐inducible Dek mice ( iDek and iDek‐e mice respectively). Both DOX+ iDek and iDek‐e mice did not show differences in the oral mucosa compared with DOX‐ mice. In the environment exposed to carcinogen, DOX‐treated (DOX+) iDek mice showed field cancerization and OSCC development. Microarray analysis revealed that DEK overexpression was mediated by the upregulation of DNA replication‐ and cell cycle‐related genes, particularly those related to the G 1 / S transition. Tongue tumors overexpressing DEK showed increased proliferating cell nuclear antigen and elongator complex protein 3 expression. Our data suggest that DEK overexpression enhanced carcinogenesis, including field cancerization, in OSCC by stimulating the G 1 / S phase transition and promoting DNA replication, providing important insights into the potential applications of DEK as a target in the treatment and prevention of OSCC. Abstract : Representative images of IHC analysis for detection of PCNA in the tongues of 4NQO‐treated mice with or without DOX (DOX+ and DOX‐ respectively). Scale bars, 40 μ m. PCNA‐positive cells in DOX+ iDek mice were spread to the upper layer of the epithelium and the PCNA‐positive index in DOX+ iDek mice was significantly higher than that in DOX‐ iDek mice.