Circadian Clock Disruption and Colorectal Cancer

项目总结/摘要 结直肠癌（CRC）是癌症相关死亡的第三大原因， 是美国第三常见的癌症尽管有这些优势 早期发现的息肉筛查，晚期CRC的治疗选择依赖于 积极的化疗因此，用于治疗CRC的靶向疗法是 急需的。引人注目的是，临床证据表明，与正常人相比， 在肠组织中，人结肠直肠肿瘤表现出基因表达的下调 生物钟分子机器的所有组成部分。生物钟是 内源性生物起搏器控制多种生理、内分泌和 代谢过程的运作，以维持生物体内平衡在一个严格的24- 小时周期。有证据表明，昼夜节律的紊乱 导致癌症，但精确的分子机制和详细的信号传导 途径尚未阐明。此外，生物钟和生物钟之间的串扰 肠内的增殖途径还没有完全阐明，更具体地说， 这种串扰如何参与体内CRC的起始和进展仍是未知的 悬而未决为了解决这一知识差距，我们已经产生了一种新的基因 工程小鼠模型（GEMM），以阐明生物钟中断的影响 对肠细胞增殖和结直肠癌的影响我们认为， 分子时钟机制异常地驱动肠中的Wnt/b-连环蛋白信号传导。 这项提案的一个目标是描绘生物钟在Wnt上的作用， 肠内依赖性增殖途径，包括 引发癌症的细胞群。该提案的第二个目标是定义 生物钟如何影响Wnt/b-连环蛋白依赖性的分子机制 转录和表观遗传途径。我们的研究具有重要的临床意义 在分子水平上， 改变肿瘤发生和疾病进展至CRC。这些发现提供了新的 深入了解生物钟治疗靶向治疗的潜力， CRC，以及依赖于激活的Wnt信号传导的其他肿瘤类型。

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is the third leading cause of cancer-related deaths and the third most commonly diagnosed cancer in the United States. Despite the advantages of polyp screening for early detection, treatment options for advanced CRC rely on aggressive chemotherapy. Therefore, targeted therapy for the treatment of CRC is critically needed. Strikingly, clinical evidence has shown that compared to normal intestinal tissue, human colorectal tumors exhibit a down-regulation of gene expression of all components of the circadian clock molecular machinery. The circadian clock is the endogenous biological pacemaker which controls several physiological, endocrine and metabolic processes that operate to maintain organismal homeostasis within a strict 24- hour period. Several lines of evidence suggest that disruption of circadian rhythms results in cancer, yet the precise molecular mechanisms and detailed signaling pathways have yet to be elucidated. Moreover, the crosstalk between the circadian clock and proliferative pathways in the intestine is not fully elucidated, and more specifically, how this crosstalk is involved in CRC initiation and progression in vivo remains unresolved. To address this knowledge gap, we have generated a novel genetically engineered mouse model (GEMM) to elucidate the effects of circadian clock disruption on intestinal cell proliferation and CRC. We propose that genetic disruption of the molecular clock machinery aberrantly drives Wnt/b-Catenin signaling in the intestine. One goal of this proposal is to delineate the role of the circadian clock on Wnt- dependent proliferation pathways in the intestine, including pathways that govern cancer-initiating cell populations. A second goal of this proposal is to define the molecular mechanism of how the circadian clock impinges on Wnt/b-Catenin dependent transcriptional and epigenetic pathways. Our studies have important clinical implications in understanding how disruption of the biological pacemaker, on the molecular level, alters tumor initiation and disease progression to CRC. These findings provide novel insight into the potential for therapeutic targeting of the circadian clock for treatment of CRC, in addition to other tumors types dependent on activated Wnt signaling.