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（由申请人提供）：皮肤恶性黑色素瘤的发病率持续上升，预防仍然是对抗这种疾病的最佳途径，但由于缺乏对黑色素瘤形成机制的了解，有效的预防策略受到阻碍。导致表皮黑色素细胞（hMCs）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中角质形成细胞转化的致癌途径不同。虽然角化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，但这种突变在黑色素瘤中很少见。虽然有令人信服的证据表明紫外线辐射（UVR）的作用，但对于至少一部分出现在身体阳光照射区域的黑色素瘤肿瘤，由UVR直接诱导的DNA光产物似乎并不是黑色素瘤相关基因遗传改变的主要原因。p16和BRAF基因突变被认为是由氧化应激诱导的，这强调了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。研究对抗uvr诱导的hmc氧化应激的机制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。本研究的目的是验证一个中心假设，即a-黑色素细胞刺激激素（a-MSH）是一种重要的旁分泌因子，是黑色素生成（即晒黑）对太阳辐射的反应所必需的，通过减少活性氧（ROS）的产生、增加抗氧化蛋白的表达和/或活性，以及增强氧化DNA损伤的修复，保护黑素细胞免受紫外线辐射的致癌作用。我们提出了两个具体目的：1)验证a-MSH通过调节转录因子nf - e2相关因子（Nrf-2）的活性来发挥其抗氧化作用的假设；2)验证p53的积累和转录活性是a-MSH减少DNA氧化损伤所必需的假设。这一建议将定义a- msh在UVR光保护hmc中的新作用，超越其作为黑素生成诱导剂的经典作用，并包括减少紫外线诱导的DNA氧化损伤，作为可能的主要保护机制。公共卫生相关性：皮肤恶性黑色素瘤是最致命的皮肤癌，其发病率持续上升。本研究的目的是证明a-黑色素细胞刺激激素（a-MSH）是皮肤鞣制反应的重要因素，通过减少自由基引起的负担来保护黑色素细胞免受紫外线的致癌作用。在这项研究中，我们建议研究a-MSH抵消紫外线诱导的人类黑素细胞氧化应激，从而阻止其恶性转化为黑色素瘤的分子途径。