Ethanol-induced skin changes

项目概要/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。约20万新 2020年将诊断出黑色素瘤病例。虽然一个主要的风险 紫外线（UV）暴露，并不是所有形式的黑色素瘤都与太阳有关 与黑色素瘤发病率相关的因素是 暴露或发生在阳光下 地区更好地了解与紫外线无关的风险因素将有助于开发更有效的预防措施 黑色素瘤的治疗策略最近的研究，包括我们的研究，表明酒精消费是积极的， 与黑色素瘤风险增加有关。然而，没有研究测试这种联系，并阐明 在体外和体内的机制。 酒精首先被乙醇脱氢酶（ADH）代谢为乙醛（AcAH），然后被氧化为 线粒体乙醛脱氢酶2（ALDH 2）。除了这两种主要的酶， 另一种酶，细胞色素p450 2 E1（CYP 2 E1），参与将酒精转化为AcAH，然后转化为 醋酸为了了解酒精代谢酶和黑色素瘤之间的关系，我们使用了 癌症基因组图谱（TCGA）数据库，并分析了ADH（1A，1B和1C），ALDH 2和CYP 2 E1。我们发现 ALDH 2 mRNA的低表达与黑色素瘤患者的预后不良之间存在强相关性。 ALDH 2可被多种环境因素灭活。为了了解乙醇和灭活的 在皮肤生物学中，我们使用了10周龄的Aldh 2 KO小鼠。因为癌变是一个慢性过程， 我们使用慢性酒精消耗的小鼠模型，其中提供3-5%和10%（v/v）乙醇， 唯一的饮用水。我们的初步实验揭示了一种独特的DNA损伤模式， 在Aldh 2 KO小鼠中通过乙醇进行增殖。在这项拨款申请中，我们假设乙醇和/或乙酰胆碱 诱导导致黑素细胞活化和暗CPD形成细胞应激反应，并提出 定义与乙醇诱导的小鼠皮肤变化相关的转录组（Aim 1）以及 在黑素细胞中通过乙醇/AcAH形成暗CPD（目的2）。 乙醇和/或乙醛对皮肤变化的影响还有待研究。鉴于其独特的DNA 我们的研究结果表明，乙醇诱导黑素细胞增殖和紫外线诱导的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R 01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.