An Interaction between Arsenic-Induced Epigenetic Modification and Inflammatory Promotion in a Skin Equivalent during Arsenic Carcinogenesis.
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.
Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
Wei-Ting
WT
Liao
Graduate Institute of Medical Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Jian-He
JH
Lu
Department of Dermatology, Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
Chih-Hung
CH
Lee
Department of Dermatology, Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Cheng-Che E
CE
Lan
College of Medicine, China Medical University, Taichung 404, Taiwan.
Jan-Gowth
JG
Chang
Department of Pathology, Kaohsiung Medical University and Hospital, Kaohsiung 807, Taiwan.
Chee-Yin
CY
Chai
Department of Dermatology, Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan 350, Taiwan. Electronic address: dermyu@nhri.org.tw.
Hsin-Su
HS
Yu
D017209:Apoptosis / Q000187:drug effects; D001151:Arsenic / Q000633:toxicity*; D001913:Bowen's Disease / Q000209:etiology / Q000473:pathology; D063646:Carcinogenesis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology / Q000473:pathology; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D053181:Caspase 8; D001151:Arsenic