Ethanol-induced skin changes

项目摘要/摘要 大多数癌症的发病率已经下降，但黑色素瘤的发病率继续上升。新增约200,000人 黑色素瘤病例将在2020年确诊。尽管有一个主要风险 紫外线照射，并不是所有形式的黑色素瘤都与太阳有关 与黑色素瘤发病率有关的因素是 暴晒或发生在阳光照射下 区域。更好地了解紫外线无关的风险因素将有助于开发更有效的预防措施 治疗黑色素瘤的策略。最近的研究，包括我们的研究表明，饮酒是积极的 会增加患黑色素瘤的风险。然而，还没有研究测试这种联系并阐明 体外和体内机制。 乙醇首先在乙醇脱氢酶(ADH)的作用下代谢成乙醛(AcAH)，然后被氧化成乙醛 线粒体乙醛脱氢酶2(ALDH2)。除了这两种主要的酶， 另一种酶，细胞色素P450 2E1(细胞色素P450 2E1)，参与酒精转化为AcAH，然后再转化为 冰醋酸。为了了解酒精代谢酶与黑色素瘤的关系，我们使用了 肿瘤基因组图谱(TCGA)数据库，分析ADH(1A、1B和1C)、ALDH2和CYP2E1。我们发现 ALDH2mRNAs低表达与黑色素瘤患者预后不良密切相关。 ALDH2可被多种环境因素灭活。了解乙醇和灭活剂的作用 在皮肤生物学方面，我们使用了10周大的ALDH2 KO小鼠。因为致癌是一个长期的过程， 我们使用了一种慢性酒精消费的小鼠模型，其中3-5%和10%(v/v)的乙醇作为 唯一的饮水液。我们的初步实验揭示了一种独特的DNA损伤模式和黑素细胞 乙醇对ALDH2 KO小鼠的增殖作用。在这项拨款申请中，我们假设乙醇和/或AcAH 诱导细胞应激反应，导致黑素细胞激活和暗CPD形成，并建议 确定与乙醇诱导的小鼠皮肤变化相关的转录本(目标1)及其机制 乙醇/AcAH在黑素细胞中形成暗CPD(目标2)。 乙醇和/或乙醛对皮肤变化的影响还有待研究。鉴于独一无二的DNA 紫外线损伤，乙醇诱导黑素细胞增殖和紫外线诱导DNA 没有紫外线照射的损伤需要进一步的表型、功能和机制研究，这将是 在未来的R01应用中进一步探索。

PROJECT SUMMARY/ABSTRACT The incidence of most cancers has declined, but that of melanoma continues to rise. About 200,000 new cases of melanoma will be diagnosed in 2020. Although one major risk ultraviolet (UV) exposure, not all forms of melanoma are related to sun factor linked to melanoma incidence is exposure or occur in sun-exposed areas. A better understanding of UV-unrelated risk factors will help in developing more effective preventative strategies for melanoma. Recent studies, including ours, have shown that alcohol consumption is positively linked to an increased risk of melanoma. However, no studies have tested this connection and elucidated the mechanisms in vitro and in vivo. Alcohol is first metabolized to acetaldehyde (AcAH) by alcohol dehydrogenase (ADH), and then oxidized to acetic acid by mitochondrial aldehyde dehydrogenase 2 (ALDH2). Alongside these two major enzymes, another enzyme, cytochrome p450 2E1 (CYP2E1), is involved in the conversion of alcohol to AcAH and then to acetic acid. To understand the relation between alcohol-metabolizing enzymes and melanoma, we used The Cancer Genome Atlas (TCGA) database and analyzed ADH (1A, 1B and 1C), ALDH2 and CYP2E1. We found a strong correlation between low expression of ALDH2 mRNAs and worse prognosis of melanoma patients. ALDH2 could be inactivated by many environmental factors. To understand the role for ethanol and inactivated ALDH2 in skin biology, we used ten-week-old Aldh2 KO mice. Because carcinogenesis is a chronic process, we used a mouse model of chronic alcohol consumption, where 3-5% and 10% (v/v) ethanol was provided as sole drinking fluid. Our preliminary experiments revealed a unique DNA damage pattern and melanocyte proliferation by ethanol in Aldh2 KO mice. In this grant application, we hypothesize that ethanol and/or AcAH induce cellular stress responses leading to melanocyte activation and dark CPD formation, and propose to define transcriptomes associated with ethanol-induced skin changes in mice (Aim 1) and the mechanisms of dark CPD formation by ethanol/AcAH in melanocytes (Aim 2). The effect of ethanol and/or acetaldehyde on skin changes has yet to be studied. Given the unique DNA damage induced by UV, our findings that ethanol induces melanocyte proliferation and UV-induced DNA damage without UV exposure warrant further phenotypic, functional and mechanistic studies, which will be further explored in future R01 applications.