Defining a New Role for Alpha-MSH: Antioxidant in UVB-Irradiated Melanocytes

定义 Alpha-MSH 的新作用：UVB 照射的黑素细胞中的抗氧化剂

• 批准号: 7990289
• 负责人: Ana Luisa Kadekaro
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-07 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990289
• 关键词: 8-Oxoguanine DNA Glycosylase; 8-hydroxyguanosine; 8-oxo-7,8-dihydrodeoxyguanine; Address; Advocate; Antioxidants; Area; Awareness; BRAF gene; Binding; CDKN2A gene; Cell Nucleus; Clinical; Cutaneous Melanoma; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclobutanes; Cytoplasm; DNA Damage; DNA Repair; DNA photoproducts; DNA repair protein; Data; Disease; Enzymes; Etiology; Exhibits; Ferritin; Free Radicals; Generations; Genes; Glutathione S-Transferase; Homeostasis; Human; Hydrogen Peroxide; Incidence; Individual; Knowledge; Lead; MDM2 gene; Malignant - descriptor; Melanocortin 1 Receptor; Melanocyte stimulating hormone; Melanogenesis; Mitogen-Activated Protein Kinases; Molecular; Mutation; NAD(P)H dehydrogenase (quinone) 1, human; NF-E2-related factor 2; Nuclear Translocation; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Phase; Phosphorylation; Play; Predisposition; Prevention; Prevention strategy; Proliferating Cell Nuclear Antigen; Proteins; Public Health; Reactive Oxygen Species; Refractory; Response Elements; Role; Serine; Signal Pathway; Skin; Skin Cancer; Skin tanning; Solar Energy; Squamous cell carcinoma; Sun Exposure; Susceptibility Gene; TP53 gene; Testing; The Sun; Transcend; Tumor-Derived; UV induced; Ultraviolet Rays; alpha-Melanocyte stimulating hormone; base; carcinogenesis; catalase; dimer; environmental stressor; fight against; heme oxygenase-1; inhibitor/antagonist; keratinocyte; loss of function; melanocyte; melanoma; novel; nuclear factor-erythroid 2; nutlin 3; oxidative DNA damage; paracrine; photoprotection; pifithrin; prevent; programs; promoter; public health relevance; repaired; replication factor A; response; small hairpin RNA; transcription factor; tumor; ultraviolet irradiation

DESCRIPTION (provided by applicant): Cutaneous malignant melanoma incidence continues to rise, and prevention is still the best way to fight against the disease, yet efficient prevention strategies are hindered by the lack of knowledge of the mechanisms involved in melanomagenesis. The carcinogenic pathways that lead to the malignant transformation of epidermal melanocytes (hMCs) to melanoma seem to differ from those that lead to the transformation of keratinocytes in basal or squamous cell carcinoma tumors. While keratinocyte-derived tumors commonly present typical "UV signature" mutations, particularly in the TP53 gene, such mutations are rare in melanoma tumors. Although there is compelling evidence for the role of ultraviolet radiation (UVR), for at least a subset of melanoma tumors that arise in sun exposed areas of the body, DNA photoproducts that are directly induced by UVR, do not seem to be the main cause for the genetic alterations in melanoma-associated genes. Mutations in p16 and BRAF genes, which are suggested to be induced by oxidative stress, underscore the central role of UVR-induced oxidative stress in hMC malignant transformation to melanoma. Studies addressing the mechanisms that counteract UVR-induced oxidative stress in hMCs, have important clinical and public health implications since they should provide novel means for melanoma prevention strategies. The objective of this proposal is to test the central hypothesis that a-melanocyte stimulating hormone (a-MSH), an important paracrine factor that is required for melanogenic (i.e. tanning) response to solar radiation, protects melanocytes from the carcinogenic effect of UVR by reducing the generation of reactive oxygen species (ROS), increasing the expression and/or activity of antioxidant proteins, and enhancing the repair of oxidative DNA damage. We propose two specific aims: 1) to test the hypothesis that a-MSH exerts its antioxidant effects by modulating the activity of the transcription factor NF-E2-related factor (Nrf-2) and 2) to test the hypothesis that accumulation and transcriptional activity of p53 are necessary for a-MSH reduction of oxidative DNA damage. This proposal will define a new role for a-MSH in UVR photoprotection of hMCs that transcends its classically known effect as an inducer of melanogenesis, and includes reduction of UV-induced oxidative DNA damage, as a possible primary protective mechanism. Public Health Relevance: The incidence of cutaneous malignant melanoma, the deadliest form of skin cancer, continues to rise. The objective of this study is to demonstrate that a-melanocyte stimulating hormone (a-MSH), an important factor for tanning response in the skin, protects melanocytes from the carcinogenic effect of UV by reducing the burden caused by free radicals. In this study, we are proposing to investigate the molecular pathways by which a-MSH counteracts the UV-induced oxidative stress in human melanocytes, and thus prevents their malignant transformation to melanoma.

描述（申请人提供）：皮肤恶性黑色素瘤发病率持续上升，预防仍然是对抗该疾病的最佳方法，但由于缺乏对黑色素瘤发生机制的了解，有效的预防策略受到阻碍。导致表皮黑色素细胞（hMC）恶性转化为黑色素瘤的致癌途径似乎与导致基底细胞癌或鳞状细胞癌肿瘤中角质形成细胞转化的致癌途径不同。虽然角质细胞衍生的肿瘤通常呈现典型的“紫外线特征”突变，特别是在 TP53 基因中，但此类突变在黑色素瘤中很少见。尽管有令人信服的证据证明紫外线辐射 (UVR) 的作用，但对于身体暴露于阳光区域的至少一部分黑色素瘤来说，由 UVR 直接诱导的 DNA 光产物似乎并不是主要原因用于黑色素瘤相关基因的遗传改变。 p16 和 BRAF 基因突变被认为是由氧化应激诱导的，强调了 UVR 诱导的氧化应激在 hMC 恶性转化为黑色素瘤中的核心作用。针对 hMC 中抵抗 UVR 诱导的氧化应激机制的研究具有重要的临床和公共卫生意义，因为它们应该为黑色素瘤预防策略提供新的手段。该提案的目的是检验中心假设，即 a-促黑素细胞激素 (a-MSH) 是对太阳辐射产生黑色素（即晒黑）反应所需的重要旁分泌因子，可通过以下方式保护黑素细胞免受 UVR 的致癌作用：减少活性氧 (ROS) 的产生，增加抗氧化蛋白的表达和/或活性，并增强氧化 DNA 损伤的修复。我们提出了两个具体目标：1) 检验 a-MSH 通过调节转录因子 NF-E2 相关因子 (Nrf-2) 的活性发挥其抗氧化作用的假设，2) 检验积累和转录作用的假设p53 的活性对于 a-MSH 减少氧化性 DNA 损伤是必需的。该提案将定义 a-MSH 在 hMC 的 UVR 光保护中的新作用，超越其作为黑色素生成诱导剂的传统已知作用，并包括减少 UV 诱导的氧化 DNA 损伤，作为一种可能的主要保护机制。公共健康相关性：皮肤恶性黑色素瘤（最致命的皮肤癌）的发病率持续上升。本研究的目的是证明，a-促黑素细胞激素 (a-MSH) 是皮肤晒黑反应的重要因素，可通过减轻自由基造成的负担，保护黑素细胞免受紫外线的致癌作用。在这项研究中，我们打算研究a-MSH对抗紫外线诱导的人类黑色素细胞氧化应激的分子途径，从而防止其恶性转化为黑色素瘤。