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

Abstract

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.

Role of the DEK oncogene in the development of squamous cell carcinoma

“…DEK protein expression was higher in OSCC tissues than in the normal tissues, and the percentage of positive cells was > 50% in almost all samples (30/34 cases) [19]. These Recently, two DEK-overexpressing murine models have been reported [19,45]. Matrka et al [45] established a tetracycline-inducible DEK transgenic mouse model to investigate whether DEK contributes to carcinogenesis in vivo.…”

“…These Recently, two DEK-overexpressing murine models have been reported [19,45]. Matrka et al [45] established a tetracycline-inducible DEK transgenic mouse model to investigate whether DEK contributes to carcinogenesis in vivo.…”

“…Recently, two DEK-overexpressing murine models have been reported [ 19 , 45 ]. Matrka et al [ 45 ] established a tetracycline-inducible DEK transgenic mouse model to investigate whether DEK contributes to carcinogenesis in vivo. In the transgenic mouse model, DEK was overexpressed in specific tissues, and expression was inhibited by doxycycline.…”

“…SCC has been reported to arise from keratinocytes in the squamous epithelium, and overexpression of DEK has been shown to promote cell proliferation and transformation and inhibit apoptosis [ 11 , 46 – 48 ]. Matrka et al [ 45 ] concluded that cell differentiation, senescence, and DEK overexpression specifically targeting the basal keratinocytes can promote the proliferation of cells and the development of SCC in vivo.…”

Optical Redox Imaging Detects the Effects of DEK Oncogene Knockdown on the Redox State of MDA-MB-231 Breast Cancer Cells

“…DEK is a chromatin remodeling protein whose overexpression has been reported to reprogram cellular metabolism, stimulate cell proliferation, increase invasion and metastasis, etc [20][21][22]. In addition, high DEK expression is an independent prognostic factor associated with aggressive disease and poor outcome in solid tumors, including breast cancer [23][24][25]. The ORI results we acquired demonstrated that MDA-MB-231 cells with decreased DEK expression (DEKsh) had a significantly lower FAD redox ratio than the vector treated control cells (NTsh).…”