Abstract
The Slug transcription factor plays an important role in ultraviolet radiation (UVR)-induced skin carcinogenesis, particularly in the epithelial-mesenchymal transition (EMT) occurring during tumor progression. In the present studies, we investigated the role of Slug in two-stage chemical skin carcinogenesis. Slug and the related transcription factor Snail were expressed at high levels in skin tumors induced by 7,12-dimethylbenz[α]anthracene application followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. TPA-induced transient elevation of Slug and Snail proteins in normal mouse epidermis and studies in Slug transgenic mice indicated that Slug modulates TPA-induced epidermal hyperplasia and cutaneous inflammation. Although Snail family factors have been linked to inflammation via interactions with the cyclooxygenase-2 (COX-2) pathway, a pathway that also plays an important role in skin carcinogenesis, transient TPA induction of Slug and Snail appeared unrelated to COX-2 expression. In cultured human keratinocytes, TPA induced Snail mRNA expression while suppressing Slug expression, and this differential regulation was due specifically to activation of the TPA receptor. These studies show that Slug and Snail exhibit similar patterns of expression during both UVR and chemical skin carcinogenesis, that Slug and Snail can be differentially regulated under some conditions and that in vitro findings may not recapitulate in vivo results.
Highlights
Epithelial-mesenchymal transition (EMT) is characterized by loss of homotypic adhesion, acquisition of migratory capabilities and a switch from keratin to vimentin intermediate filament expression
We showed that ultraviolet radiation (UVR) induces expression of Slug and Snail in the epidermis, that Slug is persistently overexpressed in UVR-induced squamous cell carcinomas and that Slug modulates UVR-induced cutaneous inflammation
To determine if Slug and Snail expression was elevated in tumors induced by a two-stage DMBA/TPA protocol, we examined four DMBA/TPA-induced squamous cell carcinomas
Summary
Epithelial-mesenchymal transition (EMT) is characterized by loss of homotypic adhesion, acquisition of migratory capabilities and a switch from keratin to vimentin intermediate filament expression. EMT takes place during ultraviolet radiation (UVR) and chemically-induced skin carcinogenesis in mice, as tumors progress from a squamous to a spindle morphology. In UVR-exposed skin, as well as in non-small-cell lung and pancreatic cancer, Slug transcriptionally represses 15-hydroxyprostaglandin dehydrogenase [3,9,13,14] This enzyme catabolizes prostaglandins and reduces inflammation, acting as a tumor suppressor. The interrelationship between COX-2 and Snail family expression remains to be clarified It is clear, that COX-2 can stimulate EMT-like enhanced motility and decreased homotypic adhesion in a variety of cancer cell types [18,19,20]. We showed that UVR induces expression of Slug and Snail in the epidermis, that Slug is persistently overexpressed in UVR-induced squamous cell carcinomas and that Slug modulates UVR-induced cutaneous inflammation. Our studies indicate that COX-2 does not appear to play a role in TPA induction of Slug and Snail and highlight the finding that in vivo and in vitro studies of Slug induction may yield different results
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
