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 nm），主要负责超过1，000，000例新病例 非黑色素瘤皮肤癌每年仅在美国，使其成为最 对人类有害的环境致癌物。因此，迫切需要 需要制定战略，以防止这些皮肤的发生， 恶性肿瘤。 我们和其他人以前已经表明，多酚 从绿色茶中分离的级分，特别是其主要和最重要的级分， 有效化学预防抗氧化剂成分（-）-表没食子儿茶素-3- 没食子酸酯（EGCG），对紫外线引起的皮肤有显著的预防作用 小鼠模型中的肿瘤发生。 目前的建议旨在界定 通过口服给予SKH-1无毛小鼠EGCG的机制 防止光致癌作用。 在这方面要检验的中心假设是， 有人提出，UVB暴露于皮肤会引起氧化应激， 表皮生长因子受体（EGFR）和促分裂原的磷酸化， 活化蛋白激酶（MAPK）信号通路，导致诱导 光致癌事件 我们假设的必然结果是， 将来自饮用水中的绿色茶的膳食抗氧化剂EGCG给予SKH- l无毛小鼠将防止UVB辐射引起的氧化应激， EGFR和PK信号通路的氧化应激介导的磷酸化。 抑制UVB诱导的氧化应激介导的 通过EGCG的细胞信号传导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：（一） 确定单次或多次UVB暴露对皮肤的影响， 氧化应激，以及膳食抗氧化剂EGCG对 UVB诱导的氧化应激，和（ii）确定UVB诱导的氧化应激的影响。 氧化应激引起的EGFR磷酸化和MAPK，如 细胞外信号调节激酶（ERK 1/2）、JNK和p38信号通路 体内小鼠皮肤。 将确定EGCG对UVB的预防作用- 诱导氧化应激介导的这些细胞信号的磷酸化 事件 验证这一假设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- 诱导皮肤癌的发展，这可能会导致保护和延长 人的健康和生命。

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.