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/摘要 生物钟对环境时间线索做出反应以协调基因的24小时节律性 几乎在身体的所有细胞中都有表达和生物学过程。根据美国劳工部的说法， 约15%-20%的美国人从事轮班工作，因此改变了醒/睡的时间 打乱了它们的内源性生物钟。流行病学研究得出的结论是， 长期轮班工作患多种癌症风险增加，包括皮肤病 癌症。皮肤癌是最常见的恶性肿瘤，在美国其发病率正在急剧上升。 在致病因素中，暴露于太阳紫外线B(UVB)辐射是主要的危险因素(最高可达 90%)用于皮肤细胞的恶性转化和皮肤癌的发展。在人类和小鼠身上，核苷酸 切除修复(NER)消除了UVB造成的遗传损伤。因此，保护免受UVB照射和 确保高效的NER能力对于维持基因组稳定性和预防皮肤癌至关重要。 此前使用遗传小鼠模型进行的研究表明，生物钟调节着几种肿瘤 抑制包括NER在内的通路，这些通路对于保持基因组的稳定性和保护 环境致癌。然而，在理解昼夜节律的扰乱方面存在一个根本性的差距。 与轮班工作相关的会导致环境致癌和潜在的分子 影响人类疾病发展的机制。这种知识的缺乏是一个重要的障碍 因为它突显了对恶性转化进行机械性洞察的必要性，并代表了 预测轮班工人疾病后果的严重性。该项目的总体目标是确定 并表征了UVB的早期致癌机制和昼夜节律中断的后果- 诱发皮肤癌。我们的中心假设得到了初步数据的支持，那就是昼夜节律紊乱 破坏DNA修复能力、炎症反应和其他与遗传毒性应激相关的细胞 导致倒班工作致癌的途径。我们的研究使用昼夜同步的皮肤细胞 体外、昼夜节律紊乱和体内易发生皮肤癌的SKH-1基因小鼠模型，以及皮肤 活体受试者的样本。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。这个 目标2中描述的实验将检验轮班工作扰乱时钟如何影响昼夜节律 节奏性和内耳。在目标3中，我们将描述旋转移位是如何工作的，以及 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中断的分子路线图 并将导致识别可应用于疾病的新机制 对昼夜节律功能异常的个体进行预防。

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.