An Interaction between arsenic-induced epigenetic modification and inflammatory promotion in a skin equivalent during arsenic carcinogenesis

[[abstract]]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 cell-cell interactions involved in those processes remain unclear. We have established a human intraepidermal carcinoma skin equivalent (SE) with organotypic culture - consisting of keratinocytes (KCs), fibroblasts, and peripheral blood mononuclear cells (PBMCs) - induced by arsenic treatment. This SE demonstrates the pathognomonic characteristics of arsenic-induced Bowen's disease (As-BD), including acanthosis, dysplasia, and dyskeratosis. Using this SE 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-alpha release mainly from PBMCs. TNF-alpha triggered anti-apoptotic signals via FLIP-associated caspase-8 inactivation in arsenic-treated KCs, which in turn contributed to cell survival and aneuploidy. The interaction between arsenic-induced epigenetic modification and inflammatory promotion resulted in the development of the pathognomonic features of As-BD in this model