Circadian clock disruption: A risk factor for environmental carcinogenesis

生物钟紊乱：环境致癌的危险因素 摘要/概要 生物钟对环境时间线索的响应以协调基因中的24小时节律性 在身体的几乎所有细胞中的表达和生物过程。根据美国劳工部的数据， 大约15-20%的美国人从事轮班工作，从而改变了醒来/睡眠的时间 扰乱了他们的内源性生物钟流行病学研究得出结论， 长期轮班工作会增加患多种癌症的风险，包括皮肤癌 癌的皮肤癌是最常见的恶性肿瘤，其发病率在美国急剧增加。 其中，太阳紫外线B（UVB）辐射是主要的危险因素（高达 90%）用于皮肤细胞的恶性转化和皮肤癌的发展。在人类和小鼠中， 切除修复（NER）可以消除UVB引起的遗传损伤。因此，保护免受UVB照射， 确保有效的NER能力对于维持基因组稳定性和预防皮肤癌至关重要。 以前使用遗传小鼠模型的研究表明，生物钟调节几种肿瘤， 抑制途径，包括NER，这对保持基因组稳定性和保护免受 环境致癌作用然而，在理解昼夜节律紊乱是如何发生的方面， 与轮班工作相关的环境致癌作用， 影响人类疾病进展的机制。这种知识的缺乏是一个重要的障碍 因为它强调了对恶性转化的机械洞察的需要，并代表了对恶性转化的障碍。 预测倒班工人疾病后果的严重程度。该项目的总体目标是确定 并表征早期致癌机制和UVB中昼夜节律破坏的后果- 诱发皮肤癌。我们的中心假设得到了初步数据的支持， 破坏DNA修复能力、炎症反应和其他遗传毒性应激相关细胞 这是轮班工作致癌性的基础。我们的研究使用昼夜同步的皮肤细胞， 体外、昼夜节律紊乱和皮肤致癌倾向的SKH-1体内遗传小鼠模型和皮肤 来自人类受试者的体内样品。在目标1中，我们将确定昼夜节律如何影响太阳UVB 辐射介导的DNA损伤反应，包括DNA修复和炎症反应。的 目标2中描述的实验将研究轮班工作如何影响生物钟 节奏性和NER。在目标3中，我们将描述如何轮换工作和遗传破坏的 生物钟影响皮肤癌的发生和发展。总的来说，这些研究的结果 将提供UVB辐射介导的基因组不稳定性中昼夜节律破坏的分子路线图， 并将导致识别新的机制，可用于治疗疾病 预防生理机能异常的人。

Circadian clock disruption: A risk factor for environmental carcinogenesis Abstract/Summary Circadian clocks respond to environmental time cues to coordinate 24-hour rhythmicity in gene expression and biological processes in virtually all cells of the body. According to the US Department of Labor, ~15-20% of Americans are engaged in rotating shift work, and the resulting altered timing of wake/sleep disrupts their endogenous circadian clock. Epidemiological studies have concluded that individuals who perform long-term rotating shift work suffer from an increased risk of several cancer types, including skin cancers. Skin cancer is the most common malignancy and its incidence is increasing dramatically in the U.S. Among the contributing factors, exposure to solar ultraviolet B (UVB) radiation is the major risk factor (up to 90%) for malignant transformation of skin cells and skin cancer development. In humans and mice, nucleotide excision repair (NER) removes genetic damage caused by UVB. Therefore, protection from UVB exposure and ensuring efficient NER capacity are critical for maintenance of genomic stability and prevention of skin cancer. Previous studies using genetic mouse models have shown that the circadian clock regulates several tumor suppressing pathways, including NER, that are critical for preserving genomic stability and protection against environmental carcinogenesis. However, there is a fundamental gap in understanding how circadian disruption associated with rotating shift work leads to environmental carcinogenesis and in the underlying molecular mechanisms that influence disease progression in humans. This lack of knowledge is an important roadblock because it highlights the need for mechanistic insight into malignant transformation and represents a barrier to predicting the severity of disease outcomes in shift workers. The overall objectives of this project are to identify and characterize early stage carcinogenesis mechanisms and consequences of circadian disruption in UVB- induced skin carcinogenesis. Our central hypothesis, supported by preliminary data, is that circadian disruption undermines DNA repair capacity, inflammatory responses, and other genotoxic stress-related cellular pathways that underlie the carcinogenicity of shift work. Our studies use circadian synchronized skin cells in vitro, circadian-disrupted and skin carcinogenesis-prone SKH-1 genetic mouse models in vivo, and skin samples from human subjects in vivo. In Aim 1, we will determine how the circadian rhythm impacts solar UVB radiation-mediated DNA damage responses including DNA repair and inflammatory responses. The experiments described in Aim 2 will examine how clock disruption by rotating shift work influences circadian rhythmicity and NER. In Aim 3, we will characterize how rotating shift work and genetic disruption of the circadian clock influence skin cancer initiation and progression. Collectively, the outcomes from these studies will provide a molecular roadmap of circadian disruption in UVB radiation-mediated genomic instability and carcinogenesis and will lead to the identification of novel mechanisms that can be applied toward disease prevention in individuals with abnormal circadian function.