Prevention of photocarcinogenesis by dietary antioxidant

描述(由申请人提供)： 长期暴露于太阳紫外线(UV)辐射，特别是UVB(290- 320纳米)，主要负责100多万例新发的 非黑色素瘤皮肤癌每年仅在美国就是最多的 对人类有害的环境致癌物质。因此，有一个紧急的 需要制定策略来预防这些皮肤的发生 恶性肿瘤。我们和其他人之前已经证明了一种多酚 从绿茶中分离出来的组分，特别是它的主要和最 有效化学预防抗氧化剂成分(-)-表没食子儿茶素-3- 没食子酸(EGCG)，对紫外线皮肤有显著的预防作用 小鼠模型中的肿瘤发生。目前的提案旨在定义 EGCG对SKH-L无毛小鼠灌胃给药的作用机制 防止光致癌。将在此测试的中心假设 建议是UVB暴露在皮肤下会诱导氧化应激，从而导致 表皮生长因子受体(EGFR)和丝裂原的磷酸化- 活化蛋白激酶(MAPK)信号通路诱导血管内皮细胞死亡 光致癌事件。我们假设的推论是，口头上 将膳食抗氧化剂EGCG从饮用水中的绿茶中添加到SKH- L无毛小鼠可防止中波紫外线辐射诱导的氧化应激，从而 氧化应激介导的EGFR ANC PK信号通路的磷酸化。 中波紫外线诱导的氧化应激介导的磷酸化的抑制 EGCG的细胞信号传递将导致皮肤癌发病率的降低。 本项目拟研究的具体目标如下：(I) 确定单次或多次UVB照射对皮肤的影响 氧化应激及膳食抗氧化剂EGCG的预防作用 UVB诱导的氧化应激，以及(II)确定UVB诱导的影响 氧化应激引起的EGFR和MAPK的磷酸化，如 细胞外信号调节蛋白1/2、JNK和p38信号通路 活体小鼠皮肤。EGCG对UVB的预防作用将被确定- 诱导氧化应激介导的这些细胞信号的磷酸化 事件。验证这一假说将有助于开发新的饮食 预防太阳紫外线辐射的干预方法和未来战略- 诱导皮肤癌的发生，这可能会导致保护和延长 人类的健康和生命。

DESCRIPTION (provided by applicant): Chronic exposure to solar ultraviolet (UV) radiation, particularly UVB (290- 320 nm), is primarily responsible for more than 1,000,000 new cases of nonmelanoma skin cancer each year in the USA alone, making it the most hazardous environmental carcinogen known for humans. Thus, there is an urgent need to develop strategies to prevent the occurrence of these cutaneous malignancies. We and others have previously shown that a polyphenolic fraction isolated from green tea, and particularly its major and the most effective chemopreventive antioxidant constituent (-)-epigallocatechin-3- gallate (EGCG), has remarkable preventive effects against UV-induced skin tumorigenesis in mouse model. The current proposal is designed to define the mechanism through which oral administration of EGCG to SKH-l hairless mice prevents photocarcinogenesis. The central hypothesis to be tested in this proposal is that UVB exposure to skin induces oxidative stress, which causes phosphorylation of epidermal growth factor receptor (EGFR) and mitogen- activated protein kinase (MAPK) signaling pathways leading to the induction of photocarcinogenic events. The corollary to our hypothesis is that orally administered dietary antioxidant EGCG from green tea in drinking water to SKH- l hairless mice will prevent UVB radiation-induced oxidative stress, and thus oxidative stress-mediated phosphorylation of EGFR anc PK signaling pathways. The inhibition of UVB-induced oxidative stress-mediated phosphorylation of cellular signaling by EGCG will result in reduction of skin cancer incidence. Following specific aims are proposed to study in this project: (i) to determine the effect of single or multiple UVB exposures on cutaneous oxidative stress, and preventive effects by dietary antioxidant EGCG against UVB-induced oxidative stress, and (ii) to determine the effect of UVB-induced oxidative stress-caused phosphorylation of EGFR, and MAPK such as extracellular signal-regulated kinase (ERK1/2), JNK and p38 signaling pathways in vivo mouse skin. Preventive effects of EGCG will be determined on UVB- induced oxidative stress mediated phosphorylation of these cell-signaling events. Validation of this hypothesis would help in developing novel dietary intervention approaches and future strategies to prevent solar UV radiation- induced skin cancer development, which may result to protect and prolong the human health and lives.