Dim light at night alters pancreatic cell signaling and predisposes to pancreatic adenocarcinoma

夜间昏暗的灯光会改变胰腺细胞信号传导并易患胰腺癌

• 批准号: 9292277
• 负责人: Souhad Chbeir
• 金额: $ 16.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9292277
• 关键词: Ablation; Adoption; Adult; Amish; Apoptosis; Apoptotic; Bilateral; Blood; Breast Carcinoma; CCND1 gene; Cancer Intervention; Cell Proliferation; Cells; Circadian Dysregulation; Circadian Rhythms; Cisplatin; Colon Carcinoma; Cyclin D1; Darkness; Developed Countries; Development; Diagnosis; Disinhibition; Economic Burden; Endocrine; Environmental Pollutants; Epigenetic Process; Equilibrium; Exposure to; Future; Gene Expression; General Population; Genes; Growth; Impairment; Incidence; Insulin Resistance; Insulin-Like Growth Factor I; KRAS2 gene; Lead; Light; Lighting; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Melatonin; Metabolic Diseases; Mus; Mutation; Obesity; Oncogenic; Output; Ovarian Carcinoma; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Physiological Processes; Play; Population; Prevalence; Primary carcinoma of the liver cells; Prostate carcinoma; Publishing; Risk; Risk Factors; Rodent; Role; Signal Pathway; Signal Transduction; Sleep; TP53 gene; Testing; Therapeutic; Transgenic Mice; Treatment Cost; Tumor Suppressor Genes; Vision; Visually Impaired Persons; Woman; Work; c-myc Genes; cancer prevention; cancer type; carcinogenesis; cdc Genes; circadian pacemaker; lung Carcinoma; men; metabolic profile; notch protein; novel; outcome forecast; overexpression; pancreatic cancer cells; pancreatic neoplasm; shift work; synergism; tumor; tumor growth; tumor progression

Abstract The widespread adoption of electric lighting in industrialized countries has led to significant exposure to artificial light at night (LAN). Exposure to LAN is strongly correlated with world-wide increases in the prevalence of obesity and metabolic disorders, as well as certain types of cancers. Circadian rhythms, which rely on distinct light-dark cycles for entrainment, can be disrupted by light at night. Elevated prevalence of cancer is associated with exposure to LAN that suppresses melatonin and disrupts circadian genes expression. Circadian output plays an important role in physiological processes by controlling many genes, among which are the cell cycle genes c-MYC, WEE1, Cyclin D and p21, the tumor suppressor gene p53, as well as the apoptotic caspaces. Mutation or epigenetic silencing of the clock genes plays an important role in carcinogenesis and this may explain how disruption of circadian rhythms by shift work predisposes to breast, colon, prostate, ovarian, lung, and hepatocellular carcinomas. People working night shifts display epigenetic alteration of the Cry2 and CLOCK genes. In contrast, the incidence of cancer, including pancreatic cancer, among Old World Amish adult men and women, who are not exposed to LAN, is much lower than the general population. In addition, completely blind people have lower incidence of cancers compared to severe visually impaired people or the sighted population despite having much higher obesity rates than the Amish. Pancreatic cancer is among the most aggressive cancers with poor prognosis, short post diagnosis survival, and substantial economic burden. Night shift work can be one of the risk factors for pancreatic cancer. Circadian gene expression is dysregulated by pancreatic ductal adenocarcinoma (PDAC). K-Ras mutations account for ~90-95% of PDAC. Tumor progression in K-Ras mutation requires a cellular context, in which activation of other genes such as Notch promotes the oncogenic effect of K-Ras; Notch is controlled by the clock genes, and disruption of which in the developing pancreas alters the balance and maturity of endocrine and exocrine cells. Overexpression of the Per2 gene decreased cellular proliferation and enhanced apoptosis in pancreatic cancer cells in synergy with cisplatin treatment and bilateral ablation of the SCN in mice also resulted in accelerated growth of pancreatic tumors. The working hypothesis of this project is that light at night disrupts circadian rhythms in cell cycling genes and this disruption hastens the onset and progression of pancreatic cancer. We will test this hypothesis in two specific aims. Specific Aim 1 will examine the effects of dLAN on blood metabolic profiles, as well as clock genes, IGF-1, and cell cycle genes in the pancreases of C57BL/6J mice. The hypothesis tested in this aim is that disruption of circadian rhythms by dLAN increases body mass associated with insulin resistance and elevates IGF-1, c-myc, and cyclin D1 gene expression associated with reduced expression of the core clock genes. Specific Aim 2 will examine the effects of dLAN on progression of tumor growth and the expression levels of clock, IGF-1, and cell cycle genes in K-Ras transgenic mice. The hypothesis tested in Aim 2 is that disruption of circadian rhythms by dLAN suppresses core clock gene expression leading to disinhibition of the proliferative signaling pathways. This phenomenon leads to increased risk of tumor development in normal C57BL/6J mice or enhanced tumor growth in K-Ras transgenic mice.

抽象的 工业化国家广泛采用电灯导致 夜间（LAN）大量暴露于人造光。暴露于LAN与 肥胖和代谢性疾病的患病率在全球范围内提高，并确定 癌症类型。依靠不同的浅黑色周期夹带的昼夜节律可以 晚上被光线破坏。癌症患病率升高与暴露于LAN有关 这抑制褪黑激素并破坏昼夜节律的表达。昼夜节目的播放 通过控制许多基因，在生理过程中的重要作用，其中包括细胞 循环基因C-MYC，WEE1，细胞周期蛋白D和P21，肿瘤抑制基因p53以及 凋亡的圆圆。时钟基因的突变或表观遗传沉默起着重要作用 在癌变中，这可以解释昼夜节律的破坏 易于乳房，结肠，前列腺，卵巢，肺和肝细胞癌。人们 工作夜班显示CRY2和时钟基因的表观遗传改变。相反， 在旧世界中，包括胰腺癌在内的癌症发病率 不接触LAN的妇女远低于一般人群。此外， 与严重的视力障碍相比，完全盲人的癌症发生率较低 尽管肥胖率要高于阿米什人，但人或视力人口。 胰腺癌是预后不良的最具侵略性的癌症之一 诊断后生存和实质性的经济负担。夜班工作可能是风险之一 胰腺癌的因素。昼夜节律表达不受胰腺导管的失调 腺癌（PDAC）。 K-RAS突变占PDAC的〜90-95％。肿瘤进展 在K-Ras突变中需要一个细胞环境，其中其他基因（例如Notch）的激活 促进K-Ras的致癌作用； Notch由时钟基因控制和破坏 其中胰腺在其中改变了内分泌和外分泌的平衡和成熟度 细胞。 PER2基因的过表达降低了细胞增殖和凋亡增强 在胰腺癌细胞中与顺铂治疗协同作用和SCN的双侧消融 小鼠还导致胰腺肿瘤的生长加速。工作的假设 项目是，夜间的光线破坏了细胞循环基因中的昼夜节律和这种干扰 加快胰腺癌的发作和进展。我们将在两个中检验这一假设 具体目标。 具体目标1将检查DLAN对血液代谢谱的影响以及时钟 C57BL/6J小鼠胰腺中的基因，IGF-1和细胞周期基因。该假设检验了 在此目的是，DLAN对昼夜节律的破坏会增加与 胰岛素抵抗并提高与IGF-1，C-MYC和细胞周期蛋白D1基因表达 核心时钟基因的表达降低。 具体目标2将检查DLAN对肿瘤生长进展的影响 K-Ras转基因小鼠中时钟，IGF-1和细胞周期基因的表达水平。这 在AIM 2中检验的假设是DLAN抑制核心的昼夜节律的破坏 时钟基因表达导致抑制增殖信号通路。这 现象导致正常C57BL/6J小鼠或 K-Ras转基因小鼠的肿瘤生长增强。