Prevention of UV-carcinogenesis through DNA methylation-dependent immunomodulation

通过 DNA 甲基化依赖性免疫调节预防紫外线致癌

• 批准号: 8883008
• 负责人: SANTOSH KUMAR KATIYAR
• 金额: $ 33.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883008
• 关键词: Affect; Antigen-Presenting Cells; Arachidonic Acids; Breast; Caucasians; Cell physiology; Cells; Chemopreventive Agent; Chronic; Clinical; Colorectal Cancer; Cream; DNA; DNA Damage; DNA Methylation; DNA Modification Methylases; Data; Dendritic Cells; Development; Dinoprostone; Drug Formulations; Early Intervention; Effector Cell; Epigenetic Process; Expenditure; Exposure to; Generations; Genetic; Haptens; Healthcare; Human; Hypermethylation; Immune response; Immunosuppression; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Knowledge; Langerhans cell; Link; Magnolia; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Modification; Mus; Oral Administration; Pattern; Phytochemical; Plants; Play; Prevention; Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostate; Public Health; Risk; Risk Factors; Role; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Skin Neoplasms; Squamous cell carcinoma; Suppressor-Effector T-Lymphocytes; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Th2 Cells; Topical application; Toxic effect; UV induced; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; base; cancer diagnosis; carcinogenesis; cyclooxygenase 2; demethylation; honokiol; immunoregulation; improved; innovation; insight; keratinocyte; leukemia; lung melanoma; mouse model; novel; prevent; public health relevance; response; tumor; ultraviolet; ultraviolet irradiation

 DESCRIPTION (provided by applicant): The approximately 1.3 million new cases of nonmelanoma skin cancers diagnosed each year in the USA have a tremendous impact on public health and healthcare expenditures. Therefore, safe and effective chemopreventive strategies are urgently needed. Overexposure to solar ultraviolet (UV) radiation is a primary risk factor and that UV-induced immunosuppression plays a critical role in skin carcinogenesis. It is well established that UV irradiation induces inflammatory mediators, impairs the function of dendritic cells (DC) and effector T cells and induces suppressor T cells. UV-induced epigenetic modifications, such as DNA hypermethylation, seem to play an important role in photodamage of the skin. A model is now emerging that suggests that epigenetic modifications, including DNA hypermethylation, are induced by UVB-induced inflammatory mediators, such as cyclooxygenase-2 (COX-2)/prostaglandin E2, and act as a mechanistic link between the inflammatory mediators and compromised DC function. We have demonstrated that topical administration of honokiol, a phytochemical from the Magnolia plant, prevents both photocarcinogenesis and UVB-induced immunosuppression in mice. Our preliminary data further indicate that honokiol can correct or inhibit DNA hypermethylation in UV-exposed dendritic cells and that this restores dendritic cell-mediated activities including stimulation of cells. We propose to test the innovative hypothesis that inhibition of UVB-induced DNA hypermethylation by honokiol is critical for its chemopreventive effects on UV- induced immunosuppression. We propose three inter-related Specific Aims to test the hypothesis in a mouse model: (1) Determine whether honokiol-induced inhibition of UV-induced immunosuppression occurs through DNA demethylation in UV-exposed skin and whether the inflammatory mediators play a role in this; (2) Determine whether honokiol inhibits the development of UV-induced tolerogenic DCs and whether this is mediated through inhibition of DNA hypermethylation; and (3) Determine whether honokiol inhibition of UV- induced immunosuppression occurs through enhancement of T cell activation and whether this is mediated through inhibition of DNA hypermethylation. A combination of approaches will be utilized to verify the results including the use of COX-2 deficient mice. Innovation: The proposed studies will: (1) Identify the mechanisms by which topical or oral administration of honokiol acts to correct UV-induced immunosuppression and prevent photocarcinogenesis, thereby providing data needed for further clinical development of this promising phytochemical; and (2) The data generated will provide critical insights into the mechanisms that elicit UVB- induced DNA hypermethylation in DC and establish whether targeting of these mechanisms is sufficient to prevent UVB-induced immunosuppression. Impact: The development of new early intervention strategies using honokiol may help to reduce the risk of skin cancer in humans, as the risk of skin cancer is a major public health concern.

 描述（由申请人提供）：美国每年诊断出约 130 万新发非黑色素瘤皮肤癌病例，对公共卫生和医疗保健支出产生巨大影响。因此，迫切需要安全有效的化学预防策略。过度暴露于太阳紫外线 (UV) 辐射是主要危险因素，紫外线诱导的免疫抑制在皮肤癌发生中起着至关重要的作用。众所周知，紫外线照射会诱导炎症介质，损害树突状细胞 (DC) 和效应 T 细胞的功能，并诱导抑制性 T 细胞。紫外线诱导的表观遗传修饰，例如 DNA 高甲基化，似乎在皮肤光损伤中发挥着重要作用。目前正在出现的一个模型表明，包括 DNA 高甲基化在内的表观遗传修饰是由 UVB 诱导的炎症介质（例如环氧合酶-2 (COX-2)/前列腺素 E2）诱导的，并充当炎症介质和受损 DC 功能之间的机制联系。我们已经证明，局部施用和厚朴酚（一种来自厚朴植物的植物化学物质）可以防止小鼠的光致癌和 UVB 诱导的免疫抑制。我们的初步数据进一步表明，和厚朴酚可以纠正或抑制暴露于紫外线的树突状细胞中的 DNA 高甲基化，并且这可以恢复树突状细胞介导的活性，包括细胞刺激。我们建议测试一个创新假设，即和厚朴酚抑制 UVB 诱导的 DNA 高甲基化对于其对 UV 诱导的免疫抑制的化学预防作用至关重要。我们提出了三个相互关联的具体目标来在小鼠模型中检验这一假设：（1）确定和厚朴酚诱导的对紫外线诱导的免疫抑制的抑制是否通过紫外线暴露皮肤中的 DNA 去甲基化发生，以及炎症介质是否在其中发挥作用； (2) 确定和厚朴酚是否抑制紫外线诱导的耐受性 DC 的发育，以及这是否是通过抑制 DNA 高甲基化介导的； (3)确定和厚朴酚对紫外线诱导的免疫抑制的抑制作用是否是通过增强T细胞活化而发生的，以及这是否是通过抑制DNA高甲基化来介导的。将采用多种方法来验证结果，包括使用 COX-2 缺陷小鼠。创新：拟议的研究将：（1）确定局部或口服和厚朴酚纠正紫外线诱导的免疫抑制和预防光致癌作用的机制，从而为这种有前途的植物化学物质的进一步临床开发提供所需的数据； (2) 生成的数据将为 DC 中引发 UVB 诱导的 DNA 高甲基化的机制提供重要见解，并确定这些机制的靶向是否足以预防 UVB 诱导的免疫抑制。影响：使用和厚朴酚开发新的早期干预策略可能有助于降低人类患皮肤癌的风险，因为皮肤癌的风险是一个主要的公共卫生问题。