Circadian Clock Disruption and Colorectal Cancer

项目摘要/摘要 结直肠癌(CRC)是癌症相关死亡的第三大原因， 在美国最常见的癌症中排名第三。尽管有这些优势 息肉筛查的早期发现，晚期结直肠癌的治疗选择依赖于 激进的化疗。因此，结直肠癌的靶向治疗是 这是急需的。令人惊讶的是，临床证据表明，与正常相比 肠道组织中，人类大肠肿瘤的基因表达下调 生物钟分子机械的所有组件。昼夜节律时钟是 内源性生物起搏器，控制着几种生理、内分泌和 在严格的24小时内维持机体动态平衡的代谢过程- 一小时。多条证据表明，昼夜节律的扰乱 导致癌症，但精确的分子机制和详细的信号转导 具体途径尚不清楚。此外，生物钟之间的串扰 而肠道中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的启动和进展仍是一个未知数 悬而未决。为了解决这一知识鸿沟，我们从基因上创造了一种新的 工程化小鼠模型(GEMM)阐明生物钟干扰的影响 对肠道细胞增殖和结直肠癌的影响。我们认为，人类基因的破坏 分子时钟机制异常地驱动肠道中的Wnt/b-catenin信号。 这项提案的一个目标是描绘生物钟在WNT- 肠道中依赖的增殖途径，包括支配肠道的途径 致癌细胞群。该提案的第二个目标是定义 生物钟影响Wnt/b-catenin依赖的分子机制 转录和表观遗传途径。我们的研究具有重要的临床意义 在理解生物起搏器的破坏是如何在分子水平上， 改变肿瘤的起始和疾病进展为结直肠癌。这些发现提供了新的 深入了解以生物钟为治疗靶点治疗慢性前列腺癌的可能性 除了依赖于激活的Wnt信号的其他类型的肿瘤外，结直肠癌。

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.