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

描述(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好方法，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。导致表皮黑素细胞恶性转化为黑色素瘤的致癌途径似乎与导致基底细胞或鳞状细胞癌的角质形成细胞转化的致癌途径不同。尽管角质形成细胞来源的肿瘤通常表现出典型的“紫外线信号”突变，尤其是在TP53基因上，但这种突变在黑色素瘤肿瘤中很少见。尽管有令人信服的证据表明紫外线辐射(UVR)的作用，但对于至少一种发生在身体暴露在阳光下的黑色素瘤肿瘤来说，由UVR直接诱导的DNA光产物似乎不是黑色素瘤相关基因遗传变化的主要原因。P16和BRAF基因的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过程中的中心作用。针对HMCS中UVR诱导的氧化应激的研究具有重要的临床和公共卫生意义，因为它们将为黑色素瘤的预防策略提供新的手段。A-黑素细胞刺激素(a-MSH)是黑素细胞对太阳辐射的反应所必需的一种重要的旁分泌因子，它通过减少ROS的产生、增加抗氧化蛋白的表达和/或活性以及促进氧化DNA损伤的修复来保护黑素细胞免受UVR致癌效应的影响。我们提出了两个特定的目标：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a-MSH减少氧化DNA损伤所必需的P53的积累和转录活性的假设。这项提议将定义a-MSH在HMCS的UVR光保护中的新作用，超越其作为黑素合成诱导剂的经典已知作用，并包括减少UV诱导的氧化DNA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皮肤癌中最致命的一种，其发病率持续上升。这项研究的目的是证明a-黑素细胞刺激素(a-MSH)是皮肤晒黑反应的重要因素，通过减轻自由基造成的负担来保护黑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通过哪些分子途径来中和紫外线诱导的人类黑素细胞的氧化应激，从而防止它们向黑色素瘤的恶性转化。

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.