An Interaction between Arsenic-Induced Epigenetic Modification and Inflammatory Promotion in a Skin Equivalent during Arsenic Carcinogenesis

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• 作者：Wei-Ting Liao¹ ; ² ; ⁹ ; Jian-He Lu³ ; ⁹ ; Chih-Hung Lee⁴ ; Cheng-Che E. Lan⁵ ; Jan-Gowth Chang⁶ ; Chee-Yin Chai⁷ ; Hsin-Su Yu⁵ ; ⁸ ; ^{dermyu@nhri.org.tw}
• 关键词：As-BD ; arsenic-induced Bowen&rsquo ; s disease ; CK ; cytokeratin ; FB ; fibroblast ; H3K9 ; histone-3 lysine-9 ; KC ; keratinocyte ; PBMC ; peripheral blood mononuclear cell ; TGF-β ; transforming growth factor-beta ; TNF-α ; tumor necrosis factor-alpha ; TNF-Ab ; anti-TNF neutralizing antibody ; SE ; skin equivalent
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：137
• 期：1
• 页码：187-196
• 全文大小：2897 K
• 卷排序：137

文摘

Animal studies have shown that chemical carcinogenesis consists of a three-stage process: initiation, promotion, and progression. However, because of 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 with organotypic culture—consisting of keratinocytes, fibroblasts, and peripheral blood mononuclear cells — induced by arsenic treatment. This SE shows the pathognomonic characteristics of arsenic-induced Bowen’s disease, including acanthosis, dysplasia, and dyskeratosis. Using this SE model, we showed that arsenic initiated SUV39H2-mediated epigenetic modification of E2F1, which induced centrosome amplification in keratinocytes in 2 days; this, however, led to caspase-8–mediated apoptosis in 10 days. In parallel, arsenic stimulated tumor necrosis factor-α release mainly from peripheral blood mononuclear cells. Tumor necrosis factor-α triggered anti-apoptotic signals via FLIP-associated caspase-8 inactivation in arsenic-treated keratinocytes, 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 arsenic-induced Bowen’s disease in this model.