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3445266 
Journal Article 
A synergism between arsenic-induced epigenetic modification and inflammatory promotion in a novel skin equivalent during arsenic carcinogenesis 
Liao, W; Lu, J; Lee, C; Lan, C; Chang, J; Chai, C; Yu, H 
2016 
Yes 
Journal of Investigative Dermatology
ISSN: 0022-202X
EISSN: 1523-1747 
136 
9 
S237-S237 
English 
WOS:000383091900444 
Animal studies have shown that chemical carcinogenesis consists of a 3-stage process: initiation, promotion, and progression. However, due to the lack of a suitable tissue model, the molecular mechanisms of cellecell interactions involved in those processes remain unclear. We have established a novel human intraepidermal carcinoma skin equivalent with organotypic culture-consisting of keratinocytes (KCs), fibroblasts, and peripheral blood mononuclear cells (PBMCs)-induced by arsenic treatment. This skin equivalent demonstrates the pathognomonic characteristics of arsenic-induced Bowen’s disease (As-BD), including acanthosis, dysplasia, and dyskeratosis. Using this skin-equivalent model, we demonstrated that arsenic initiated SUV39H2-mediated epigenetic modification of E2F1, which induced centrosome amplification in KCs in 2 days; this, however, led to caspase-8 mediated apoptosis in 10 days. In parallel, arsenic stimulated TNF-a release from PBMCs. TNF-a triggered anti-apoptotic signals via FLIPassociated caspase-8 inactivation in arsenic-treated KCs, which in turn contributed to cell survival and aneuploidy. The synergism between arsenic-induced epigenetic modification and inflammatory promotion resulted in the development of the pathognomonic features of As-BD in this novel model.