title: The transcription factor Snail expressed in cutaneous squamous cell carcinoma induces epithelial-mesenchymal transition and down-regulates COX-2.
abstract: Cutaneous spindle cell squamous cell carcinoma (SCC) is a rare, but highly malignant variant of SCC. The presence of spindle-shaped cells with a sarcomatous appearance, which are derived from squamous cells, suggests that these cells are produced as a result of epithelial-mesenchymal transition (EMT). EMT is a complex process in which epithelial cells lose their polarity and cell-cell contacts, while also acquiring increased motility and invasiveness. Snail regulates EMT by binding to proximal E-boxes in the promoter region of E-cadherin and repressing its transcription. When examining the expression of EMT markers and Snail in spindle cell SCCs, we found that cyclooxygenase-2 (COX-2) expression was down-regulated. Since it has been shown that COX-2 is constitutively overexpressed in a variety of malignancies, including colon, gastric, and lung carcinomas, the down-regulation of COX-2 expression was unexpected. The presence of E-box-like sequences in the promoter region of COX-2 prompted us to perform a more detailed analysis. We introduced a Snail expression vector into keratinocyte-derived cell lines (HaKaT, HSC5, and A431 cells), and isolated stable transfectants. We determined that COX-2 expression was down-regulated in cells expressing Snail. Consistent with these observations, reporter assays revealed that COX-2 promoter activity was repressed upon Snail overexpression. Thus Snail down-regulates COX-2 in these cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Shimokawa
authors.forename: Misako
authors.initials: M
authors.lastname: Haraguchi
authors.forename: Wakako
authors.initials: W
authors.lastname: Kobayashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Higashi
authors.forename: Shigeto
authors.initials: S
authors.lastname: Matsushita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kawai
authors.forename: Takuro
authors.initials: T
authors.lastname: Kanekura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ozawa
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human