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（通过应用程序提供）：非黑色素瘤皮肤癌是美国最常见的癌症类型，每年有超过100万例新病例，同时增加对阳光（UV）的暴露（UV）和环境致癌物似乎是主要的基因制造商。该应用的长期目标是使用相对无毒的饮食癌症化合物制定安全有效的策略，以预防皮肤癌。这些研究的基本原理是基于我们实验室和其他研究的投资，表明：（1）Sulforaphane（SFN）分别在这些浆果和十字架中表现出来，在体内各种小鼠模型中都强烈抑制皮肤致癌作用； （2）在NRF2的敲除中，皮肤致癌作用得到了极大的增强，NRF2的转录因子在介导抗氧化应激/炎症反应中至关重要，并且重要的是，SFN在这些NRF2（ - / - ）小鼠中没有癌症保护作用； （3）NRF2（+/+）小鼠的皮肤肿瘤中NRF2和NRF2靶向的HO-1表达降低； （4）在所有皮肤肿瘤中都可以看到C-Myc，Bcl-2，Cyclin D1，Beta-catenin，VEGF，COX-2和BAX的表达； （5）与NRF2（+/+）小鼠相比，NRF2（ - / - ）小鼠皮肤中炎症生物标志物的表达增强了； （6）SFN在NRF2（+ /+）的MEF（小鼠胚胎成纤维细胞）和MEK（小鼠表皮角膜细胞）中诱导细胞抗氧化剂蛋白，但不是NRF2（ - / - ）； （7）SFN阻断了C57BL/6J小鼠中TPA诱导的耳朵感染，而不是NRF2（ - / - ）小鼠； （8）乌斯卡酸（UA），一种具有潜在抗炎和癌症预防活性的天然三萜类化合物，抑制了TPA诱导的耳水肿和肿瘤促进； （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的癌症发展和进展中起着重要作用。 UA和SFN均修饰JB6小鼠表皮细胞系中NRF2的CpG甲基化； （10）在DMBA/TPA乳头状瘤与正常皮肤与UVB诱导的皮肤肿瘤与通过MEDIP-SEQ分析分析的非辐射的皮肤之间的全球DNA甲基化谱图中观察到显着差异； （11）UA和SFN抑制TPA诱导的软琼脂中的JB6转化。根据上述总结的结果，我们假设UA和SFN通过以3个特定目的改变表观遗传学修饰来防止皮肤致癌作用：（1）研究B [A] P/TPA诱导的NRF2（+/+）NRF2（+/+/+）的B/TPA诱导的B/TPA诱导皮肤癌的B [A] P/TPA诱导的皮肤癌的表观遗传事件（ UVB诱导的SKH-1小鼠皮肤肿瘤发生，癌症预防有效性以及UA和SFN的表观遗传变化； （2）检查小鼠表皮JB6和人角质形成细胞细胞的体外转化过程中的表观遗传变化以及UA和SFN对这些表观遗传变化的影响； （3）阐明在小鼠表皮JB6和人角质形成型HACAT细胞中，UA和SFN在AIM 1和2中鉴定出的AIM 1和2中鉴定在AIM 1和2中的炎性/氧化应激基因的分子机制。这项研究将促进我们在开发更好的化学预防化合物中用于皮肤癌的化学预防临床试验的知识。