Prevention of UVB-induced skin cancer using sulforaphane: roles of AP-1 and Nrf2.

描述(由申请人提供)：非黑色素瘤皮肤癌(NMSC)的发病率正在上升，这是由于UVB光线穿透我们的大气等因素。皮肤癌占美国所有确诊癌症的近40%，其中大部分是NMSC。作为一名科学家，我的目标是找到新的、适用的和负担得起的局部化合物，用于降低人类NMSC的发病率。K07职业发展奖(CDA)是我开始实现这些目标并成为一名多产的顶级癌症生物学家的最有效手段。为了实现这一目标，我必须在癌症生物学和临床试验方法学方面接受过良好的培训。作为我职业发展计划的一部分，我组建了一支皮肤癌研究、小鼠研究、药物配方和临床试验方面的杰出导师团队。我将定期与我的导师互动，并接受临床试验管理、生物伦理学和生物统计学等学科的教学培训。我将参加AACR会议、皮肤癌计划项目拨款会议和癌症预防与控制研讨会。亚利桑那州癌症中心和皮肤癌研究所为我提供了独特而有价值的工具来进一步培训和实现我的目标。科学地讲，这篇CDA将帮助我研究AP-1和NRF2在UVB治疗皮肤中化学预防化合物萝卜硫素(SF)的作用机制中的作用。SF是一种在十字花科蔬菜中发现的异硫氰酸酯，在几个模型中抑制致癌作用，可能是由于诱导转录因子NFE2相关因子(NRF2)。此外，SF阻断激活蛋白-1(AP-1)转录因子的活性和DNA结合能力，AP-1是UVB诱导的皮肤癌的关键成分。我们推测，SF通过双重作用机制抑制DVB诱导的皮肤癌变，并将降低阳光损伤皮肤患者鳞状细胞癌的风险：Nrf2激活导致DNA氧化损伤减少，AP-1通过直接氧化还原调节抑制。为了验证这一假说，我们将1)测试SF对AP-1转录激活和皮肤癌变的抑制作用是否是由于与CFos和/或cJun的DNA结合结构域的化学作用；2)测试SF诱导的Nrf2对抵御UVB急性和慢性UVB诱导的小鼠皮肤损伤和慢性UVB诱导的NMSC的影响；3)测试局部应用纯化F的安全性和有效性(L/11a期临床试验)。

DESCRIPTION (provided by applicant): Non-melanoma skin cancer (NMSC) rates are rising due to factors such as increased UVB light penetrating our atmosphere. Skin cancer, the majority of which is NMSC, accounts for nearly 40% of all diagnosed cancers in the U.S. It is my goal as a scientist to find new, applicable and affordable topical compounds which will be used to reduce the incidence of NMSC in humans. A K07 Career Development Award (CDA) is the most effective means for me to begin to accomplish these objectives and become a productive top-level cancer biologist. To accomplish this goal, I must become well-trained in cancer biology and clinical trial methodology. As part of my career development plan, I have assembled a team of outstanding mentors in skin cancer research, mouse studies, drug formulation, and clinical trials. I will have regular interactions with my mentors and will receive didactic training in subjects such as clinical trial management, bioethics, and biostatistics. I will attend AACR conferences, meetings for the Skin Cancer Program Project Grant and seminars in Cancer Prevention and Control. The Arizona Cancer Center and the Skin Cancer Institute provide me with unique and valuable tools for furthering my training and accomplishing my goals. Scientifically, this CDA will help me to examine the roles of AP-1 and Nrf2 in the mechanism of action of the chemopreventive compound sulforaphane (SF) in UVB-treated skin. SF is an isothiocyanate found in cruciferous vegetables, and inhibits carcinogenesis in several models, possibly due to induction of the transcription factor Nf E2-related factor 2 (Nrf2). Additionally, SF blocks the activity and DNA-binding ability of the activator protein-1 (AP-1) transcription factor, a key component in UVB-induced skin carcinogenesis. We hypothesize that SF inhibits DVB-induced skin carcinogenesis and will reduce the risk of squamous cell carcinogenesis in patients with sun-damaged skin through a dual mechanism of action: Nrf2 activation leading to reduced oxidative DNA damage, and AP-1 inhibition through direct redox modulation. To test this hypothesis we will 1) test whether the inhibitory effect of SF on AP-1 transactivation and skin carcinogenesis is due to chemical interactions with the DNA binding domain of cFos and/or cJun; 2) test the influence of SF- induced Nrf2 on-protection against acute UVB-induced mouse skin damage and chronic UVB-induced NMSC; 3) test the safety and efficacy of topical purified F in humans (a Phase l/lla clinical trial).