Arsenic-enhanced skin carcinogenesis by UV radiation

描述（由申请人提供）：砷是一种天然存在的、广泛分布于食物、土壤和水中的元素，已被确定为多种人类肿瘤（包括肺、肝、泌尿道和皮肤肿瘤）的风险因素。无机砷被认为是一种完全致癌物，当与其他致癌物（包括紫外线辐射（UVR））结合时，还会增强肿瘤的发展。单独使用时，在非致瘤浓度下，亚砷酸盐可增强UVR刺激的皮肤癌小鼠模型中的鳞状细胞癌（SCC）。这些发现说明需要了解砷可能通过其他致癌物（包括紫外线辐射）促进肿瘤形成的机制。我们已发表的工作表明，亚砷酸盐刺激角质形成细胞中的ROS产生，并且用亚砷酸盐预处理放大氧化应激反应和信号传导。此外，亚砷酸盐预处理增强紫外线照射后的光产物和氧化DNA损伤。总之，这些研究结果表明，亚砷酸盐调节氧化应激反应的紫外线辐射，并支持目标1的研究，以调查在人类角质形成细胞暴露于亚砷酸盐和紫外线辐射单独和组合的ROS生产的性质。这将扩展到目标3中的体内研究。我们的初步研究结果表明，ROS产生的增加预计会增加氧化性DNA损伤。生化研究表明，锌指DNA修复蛋白可能是对金属毒性敏感的靶点，并代表砷致癌性的潜在机制。我们发现，i）锌指蛋白PARP-1的活性在低浓度的亚砷酸盐中受损，ii）氧化DNA损伤在PARP-1抑制剂的存在下增强，和iii）锌的包含抵消亚砷酸盐增强紫外线诱导的光产物和氧化DNA损伤。这些发现构成了目标2中进行的更详细研究的基础，这些研究将解决亚砷酸盐可能破坏DNA修复活性的机制。砷对UVR诱导的皮肤肿瘤发生的共同致癌性或协同作用的小鼠模型已得到很好的表征，这将使我们能够通过体内环境中的机械化学预防研究来测试目标1和2的特定假设（目标3）。建议的研究将解决砷作为共同致癌物的潜在机制的关键问题，并帮助我们设计有效和针对性的干预策略，以防止砷和紫外线辐射联合暴露引起的皮肤癌。

DESCRIPTION (provided by applicant): Arsenic is a naturally occurring, widely distributed element present in food, soil and water that has been identified as a risk factor for a variety of human tumors, including those of the lung, liver, urinary tract and skin. Inorganic arsenic is recognized as a complete carcinogen and additionally enhances tumor development when combined with other carcinogens including ultraviolet radiation (UVR). Arsenite enhances UVR-stimulated squamous cell carcinoma (SCC) in a murine model of skin carcinogenesis at concentrations that are non-tumorigenic when used alone. These findings illustrate the need to understand the mechanisms by which arsenic may potentiate tumor formation by other carcinogens, including UVR. Our published work shows that arsenite stimulates ROS production in keratinocytes and pretreatment with arsenite amplifies oxidative stress response and signaling. Furthermore, arsenite pretreatment enhances both photoproduct and oxidative DNA damage following UVR exposure. Together these findings suggest that arsenite modulates the oxidative stress response to UVR and supports studies in Aim 1 to investigate the nature of ROS production in human keratinocytes exposed to arsenite and UVR singly and in combination. This will be expanded to in vivo studies in Aim 3. Enhanced ROS production is predicted to increase oxidative DNA damage as supported by our preliminary findings. Biochemical studies suggest that zinc finger DNA repair proteins may be targets sensitive to metal toxicity and represent an underlying mechanism for arsenic carcinogenicity. We find that i) activity of the zinc finger protein PARP-1 is impaired at low concentrations of arsenite, ii) oxidative DNA damage is enhanced in the presence of PARP-1 inhibitor, and iii) inclusion of zinc counteracts arsenite-enhancement of UVR-induced both photoproduct and oxidative DNA damage. These findings form the foundation of more detailed studies to be conducted in Aim 2 that will address mechanisms by which arsenite may disrupt DNA repair activity. A mouse model of co-carcinogenicity or synergism of arsenic for UVR induced skin tumorigenesis has been well characterized which will allow us to test the specific hypotheses of Aims 1&2 through mechanistic chemoprevention studies in an in vivo setting (Aim 3). The proposed studies will address the critical issue of underlying mechanisms of arsenic as a co-carcinogen and help us design effective and target-specific intervention strategies against skin cancer induced by combined exposure to arsenic and UVR.