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.
Light at night is considered an environmental pollutant and it is associated with world-wide increases in the prevalence of obesity and metabolic disorders, as well as certain types of cancers. Exposure to light prior to sleep or during sleep may disrupt circadian signals impairing cell signaling and increase the onset or progression of pancreatic cancer. Our working hypothesis is that the increase in pancreatic adenocarcinoma rates reflects circadian dysregulation provoked by exposure to dim short-wavelength light at night. This hypothesis goes in line with previously published studies on the impact of shift work on cancer development. By studying nocturnal rodents we will establish the link between disrupted circadian organization by environmental light-dark cycles and an increased risk for pancreatic adenocarcinoma in the absence of disrupted sleep. This work may lead to simple, low cost treatment options for cancer prevention and intervention and suggest future novel and important therapeutic options using circadian clock modulators for pancreatic adenocarcinoma.
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