Prevention of skin cancer by phytochemicals via Nrf2 and epigenetics

通过 Nrf2 和表观遗传学使用植物化学物质预防皮肤癌

• 批准号: 9207083
• 负责人: Ah-Ng Tony Kong
• 金额: $ 35.46万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-13 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207083
• 关键词: Agar; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; BCL2 gene; Back; Benchmarking; Berry; Biological Markers; Carcinogenicity Tests; Cell Line; Cells; Chemopreventive Agent; Clinical Trials; Coupled; Cyclin D1; DNA Methylation; Development; Diet; Dietary Phytochemical; Disease; Ear; Edema; Embryo; Environmental Carcinogens; Enzymes; Epigenetic Process; Event; Exposure to; Fibroblasts; Future; Genes; Goals; Healthcare; Human; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knock-out; Knowledge; Laboratories; MEKs; Malignant Neoplasms; Mediating; Methylation; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Oxidative Regulation; Oxidative Stress; Papilloma; Pathogenesis; Pathway interactions; Phytochemical; Play; Prevalence; Prevention strategy; Preventive; Process; Proteins; Publishing; Regimen; Role; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Skin Neoplasms; Sulforaphane; Sunlight; Testing; Transcriptional Activation; Tumor Promotion; UVB carcinogenesis; UVB induced; Ultraviolet B Radiation; United States; Vascular Endothelial Growth Factors; base; beta catenin; c-myc Genes; cancer chemoprevention; cancer type; care burden; dimethylbenzanthracene; epigenetic marker; epigenetic regulation; epigenomics; genome wide methylation; in vivo; in vivo Model; insight; keratinocyte; mouse model; novel; prevent; protective effect; public health relevance; skin cancer prevention; success; transcription factor; tumorigenesis; ursolic acid

 DESCRIPTION (provided by applicant): Non-melanoma skin cancers are the most common types of cancers in the United States, with over 1 million new cases per year, while increasing exposure to sunlight (UV) and environmental carcinogens appear to be the major causative factors. The long term goal of this application is to develop a safe and effective strategy using relatively non-toxic dietary cancer chemopreventive compounds to prevent skin cancer. The rationale for these studies is based on investigation from our laboratory and others, showing that: (1) Sulforaphane (SFN) presents abundantly in these berries and crucifers, respectively, strongly inhibits skin carcinogenesis in various mouse models in vivo; (2) Skin carcinogenesis is greatly enhanced in knockouts of Nrf2, a transcription factor critical in mediating anti-oxidative stress/inflammatory responses, and, importantly, SFN has no cancer protective effect in these Nrf2(-/-) mice; (3) Nrf2 and Nrf2-targeted HO-1 expression is decreased in skin tumors in Nrf2(+/+) mice; (4) Enhanced expression of c-Myc, Bcl-2, cyclin D1, beta-catenin, VEGF, Cox-2, and Bax is seen in all skin tumors; (5) UVB enhanced expression of inflammatory biomarkers in the skin of Nrf2(-/-) mice is substantially decreased compared with Nrf2(+/+) mice; (6) SFN induces cellular antioxidant proteins in MEFs (mouse embryonic fibroblast) and MEKs (mouse epidermal keratinocytes) of Nrf2 (+/+) but not of Nrf2 (- /-); (7) SFN blocks TPA-induced ear inflammation in C57BL/6J mice and not in Nrf2(-/-) mice; (8) Ursolic acid (UA), a natural triterpenoid with potent anti-inflammatory and cancer preventive activities inhibits TPA-induced ear edema and tumor promotion; (9) Increasing evidence suggests that epigenetics plays an important role in cancer development and progression including non-melanoma skin cancer; both UA and SFN modify CpG methylation of Nrf2 in JB6 mouse epidermal cell line; (10) Significant difference are observed in global DNA methylation profiles between DMBA/TPA papilloma vs normal skin and UVB-induced skin tumor vs non- irradiated skin analyzed by MeDIP-Seq analysis; and (11) UA and SFN inhibit TPA-induced JB6 transformation in soft agar. Based on the results summarized above we hypothesize that UA and SFN prevent skin carcinogenesis by altering epigenetic modifications with 3 specific aims: (1) To investigate the epigenetic events during in vivo skin cancer development and progression in B[a]P/TPA-induced skin carcinogenesis in Nrf2(+/+) vs Nrf2(-/-) C57BL6 mice, UVB-induced skin tumorigenesis in SKH-1 mice, and the cancer preventive efficacy coupled with epigenetic changes of UA and SFN; (2) To examine the epigenetic changes during transformation in vitro of mouse epidermal JB6 and human keratinocyte HaCaT cells and the effect of UA and SFN on these epigenetic changes; (3) To elucidate the molecular mechanisms involved in the epigenetic regulation of inflammatory/oxidative stress genes identified in Aims 1 and 2 by UA and SFN in mouse epidermal JB6 and human keratinocyte HaCaT cells. This study will advance our knowledge in developing better chemopreventive compounds for cancer chemoprevention clinical trials in skin cancer.

 描述（由申请人提供）：非黑色素瘤皮肤癌是美国最常见的癌症类型，每年新增病例超过 100 万，而日光 (UV) 和环境致癌物暴露的增加似乎是主要原因该应用的长期目标是开发一种安全有效的策略，使用相对无毒的饮食癌症化学预防化合物来预防皮肤癌。这些研究的基本原理是基于我们实验室和其他人的调查显示。研究表明：(1) 萝卜硫素 (SFN) 分别大量存在于这些浆果和十字花科植物中，在体内的各种小鼠模型中强烈抑制皮肤癌的发生；(2) Nrf2 的敲除大大增强了皮肤癌的发生，Nrf2 是介导抗癌的关键转录因子。 -氧化应激/炎症反应，而且重要的是，SFN 对这些 Nrf2(-/-) 小鼠没有癌症保护作用；(3) Nrf2 和 Nrf2 靶向小鼠； Nrf2(+/+)小鼠皮肤肿瘤中HO-1表达降低；(4)c-Myc、Bcl-2、cyclin D1、β-catenin、VEGF、Cox-2和Bax表达增强；所有皮肤肿瘤；（5）与Nrf2（+/+）小鼠相比，Nrf2（-/-）小鼠皮肤中UVB增强的炎症生物标志物表达显着降低；诱导 Nrf2 (+/+) 的 MEF（小鼠胚胎成纤维细胞）和 MEK（小鼠表皮角质形成细胞）中的细胞抗氧化蛋白，但不诱导 Nrf2 (- /-) 的细胞抗氧化蛋白；(7) SFN 阻断 C57BL/6J 小鼠中 TPA 诱导的耳部炎症Nrf2(-/-) 小鼠中没有；(8) 熊果酸 (UA)，一种具有有效抗炎和抗癌功效的天然三萜类化合物(9) 越来越多的证据表明，表观遗传学在包括非黑色素瘤皮肤癌在内的癌症发生和进展中发挥重要作用；UA 和 SFN 都会改变 JB6 小鼠表皮细胞中 Nrf2 的 CpG 甲基化。线；(10) 在 DMBA/TPA 乳头状瘤与正常皮肤以及 UVB 诱导的皮肤肿瘤与非皮肤肿瘤之间观察到整体 DNA 甲基化谱存在显着差异。 (11) UA 和 SFN 抑制软琼脂中 TPA 诱导的 JB6 转化 根据上面总结的结果，我们发现 UA 和 SFN 通过改变表观遗传修饰来预防皮肤癌变，其具体目的有 3 个： (1) Nrf2(+/+) 与 B[a]P/TPA 诱导的皮肤癌发生过程中体内皮肤癌发生和进展过程中的表观遗传事件Nrf2(-/-) C57BL6小鼠、UVB诱导SKH-1小鼠皮肤肿瘤发生，以及UA和SFN的表观遗传变化对癌症的预防作用；(2)检测小鼠表皮JB6体外转化过程中的表观遗传变化；和人角质形成细胞HaCaT细胞以及UA和SFN对这些表观遗传变化的影响（3）阐明参与表观遗传调控的分子机制； UA 和 SFN 在小鼠表皮 JB6 和人角质形成细胞 HaCaT 细胞中鉴定出目标 1 和 2 中的炎症/氧化应激基因。这项研究将增进我们在开发更好的化学预防化合物用于皮肤癌化学预防临床试验方面的知识。