Dek overexpression in murine epithelia increases overt esophageal squamous cell carcinoma incidence

Esophageal cancer occurs as either squamous cell carcinoma (ESCC) or adenocarcinoma. ESCCs comprise almost 90% of cases worldwide, and recur with a less than 15% five-year survival rate despite available treatments. The identification of new ESCC drivers and therapeutic targets is critical for impro...

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Published in:	PLoS genetics Vol. 14; no. 3; p. e1007227
Main Authors:	Matrka, Marie C, Cimperman, Katherine A, Haas, Sarah R, Guasch, Geraldine, Ehrman, Lisa A, Waclaw, Ronald R, Komurov, Kakajan, Lane, Adam, Wikenheiser-Brokamp, Kathryn A, Wells, Susanne I
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 14-03-2018 Public Library of Science (PLoS)
Subjects:	4-Nitroquinoline-1-oxide - toxicity Animals Biology and Life Sciences Cancer Carcinoma, Squamous Cell - chemically induced Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - pathology Care and treatment Development and progression DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Epithelium - pathology Esophageal cancer Esophageal Neoplasms - chemically induced Esophageal Neoplasms - genetics Esophageal Neoplasms - pathology Esophageal Squamous Cell Carcinoma Gene expression Gene Expression Regulation, Neoplastic Genetic aspects Health aspects Keratinocytes - pathology Life Sciences Medicine and Health Sciences Mice, Transgenic Oncogene Proteins - genetics Oncogene Proteins - metabolism Oncogenes Poly-ADP-Ribose Binding Proteins - genetics Poly-ADP-Ribose Binding Proteins - metabolism Research and Analysis Methods Response Elements - drug effects Response Elements - genetics Squamous cell carcinoma Tetracycline - pharmacology Tongue - drug effects Tongue - pathology Transgenes Tongue Hyperexpression techniques Mouse models Cancer treatment Squamous cell carcinomas Keratinocytes Epithelium Esophagus
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Summary:	Esophageal cancer occurs as either squamous cell carcinoma (ESCC) or adenocarcinoma. ESCCs comprise almost 90% of cases worldwide, and recur with a less than 15% five-year survival rate despite available treatments. The identification of new ESCC drivers and therapeutic targets is critical for improving outcomes. Here we report that expression of the human DEK oncogene is strongly upregulated in esophageal SCC based on data in the cancer genome atlas (TCGA). DEK is a chromatin-associated protein with important roles in several nuclear processes including gene transcription, epigenetics, and DNA repair. Our previous data have utilized a murine knockout model to demonstrate that Dek expression is required for oral and esophageal SCC growth. Also, DEK overexpression in human keratinocytes, the cell of origin for SCC, was sufficient to cause hyperplasia in 3D organotypic raft cultures that mimic human skin, thus linking high DEK expression in keratinocytes to oncogenic phenotypes. However, the role of DEK over-expression in ESCC development remains unknown in human cells or genetic mouse models. To define the consequences of Dek overexpression in vivo, we generated and validated a tetracycline responsive Dek transgenic mouse model referred to as Bi-L-Dek. Dek overexpression was induced in the basal keratinocytes of stratified squamous epithelium by crossing Bi-L-Dek mice to keratin 5 tetracycline transactivator (K5-tTA) mice. Conditional transgene expression was validated in the resulting Bi-L-Dek_K5-tTA mice and was suppressed with doxycycline treatment in the tetracycline-off system. The mice were subjected to an established HNSCC and esophageal carcinogenesis protocol using the chemical carcinogen 4-nitroquinoline 1-oxide (4NQO). Dek overexpression stimulated gross esophageal tumor development, when compared to doxycycline treated control mice. Furthermore, high Dek expression caused a trend toward esophageal hyperplasia in 4NQO treated mice. Taken together, these data demonstrate that Dek overexpression in the cell of origin for SCC is sufficient to promote esophageal SCC development in vivo.
Bibliography:	new_version The authors have declared that no competing interests exist.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1007227