Promotion of cell proliferation by the proto‐oncogene DEK enhances oral squamous cell carcinogenesis through field cancerization

• Published in: Cancer medicine (Malden, MA) Vol. 6; no. 10; pp. 2424 - 2439
• Main 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
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.10.2017; John Wiley and Sons Inc
• Subjects: Animals; Cancer Prevention; Carcinogenesis; Carcinogens - administration & dosage; Carcinoma, Squamous Cell - etiology; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell cycle; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Chromosomal Proteins, Non-Histone - genetics; DEK; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA biosynthesis; DNA microarrays; Doxycycline; Dysplasia; Embryonic Stem Cells - metabolism; field cancerization; Gene Expression; Humans; Mice; Models, Biological; Mouth Neoplasms - etiology; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; Mucosa; oncogene; Oncogene Proteins - genetics; Oncogenes; Oral cancer; Oral squamous cell carcinoma; Original Research; Phase transitions; Poly-ADP-Ribose Binding Proteins - genetics; Proliferating cell nuclear antigen; Proliferating Cell Nuclear Antigen - genetics; Proliferating Cell Nuclear Antigen - metabolism; Proto-Oncogene Mas; Replication; Rodents; S phase; Senescence; Squamous cell carcinoma; Tumors; field cancerization; DEK; oncogene; squamous cell carcinoma
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.1157

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 G1/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 G1/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. 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 μm. 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.