Epigenetic Mechanisms of Biliary Epithelial Neoplasia

项目说明 胆管细胞癌(CCA)是一种高度恶性的上皮性肿瘤。 胆汁树。CCA的发病率和死亡率在全球范围内呈上升趋势，目前 没有有效的化学预防或治疗方法。分子发病机制 潜在的胆管上皮性肿瘤涉及遗传和表观遗传学变化 导致致癌和肿瘤抑制途径的改变。而当 最近的高通量下一代测序分析帮助 识别CCA的遗传异常，表观遗传学的潜在影响 胆管上皮性肿瘤的改变在很大程度上仍不清楚。 目前的建议是基于我们令人兴奋的初步研究， EZH2是一种关键的组蛋白甲基转移酶，它能在表观遗传学上沉默 抑癌基因miR-34a通过H3K27三甲基化在胆汁中的表达 肿瘤细胞，miR-34a通过靶向Notch1抑制CCA细胞生长， Notch2和Jagged1。我们的实验结果支持这样的假设，即 EZH2组蛋白甲基转移酶通过促进胆道癌的发生 MiR-34a的表观遗传沉默和随后Notch信号的激活， EZH2抑制或miR-34a替代疗法与 标准化疗方案可能是一种有效的治疗策略。 人类CCA的治疗。这些假设将分两部分进行评估。 互补的具体目标。在具体目标1中，我们将评估效果和 EZH2组蛋白甲基转移酶在胆道癌发生中的作用机制 将开展研究以确定EZH2调节的基因表达谱 以及它的作用机制。EZH2基因敲除或过度表达的影响 将在两个互补的小鼠模型中评估CCA的发展 胆管癌变(通过胆管树转导和经 流体动力尾静脉注射)。EZH2与相关信号转导的相关性 分子将在人类CCA组织和癌前胆管中得到验证 损伤。在具体目标2中，我们将评估EZH2的治疗效果 抑制或miR-34a替代联合标准化疗 CCA的临床前模型。拟议的研究将定义生物 EZH2及相关信号分子在植物体内的功能及分子机制 胆道癌的发生和发展以新表观遗传学为基础 靶向治疗。

Project Description Cholangiocarcinoma (CCA) is a highly malignant epithelial cancer of the biliary tree. The incidence and mortality of CCA is rising worldwide and currently there is no effective chemoprevention or treatment. The molecular pathogenesis underlying biliary epithelial neoplasia involves genetic and epigenetic changes leading to alterations of oncogenic and tumor suppressive pathways. While recent high throughput next-generation sequencing analyses have aided the identification of genetic abnormalities in CCA, the potential impact of epigenetic alterations on biliary epithelial neoplasia remains largely unknown. The current proposal is based on our exciting preliminary studies that EZH2 is a pivotal histone methyltransferase that epigenetically silences the expression of tumor suppressor miR-34a through H3K27 trimethylation in biliary cancer cells, and that miR-34a suppresses CCA cell growth by targeting Notch1, Notch2 and Jagged1. Our experimental findings support the hypothesis that the EZH2 histone methyltransferase promotes biliary carcinogenesis through epigenetic silencing of miR-34a and subsequent activation of Notch signaling, and that EZH2 inhibition or miR-34a replacement therapy in conjunction with standard chemotherapeutic regimen may represent an effective strategy for the treatment of human CCA. These hypotheses will be evaluated in two complementary Specific Aims. In Specific Aim 1, we will evaluate the effect and mechanism of the EZH2 histone methyltransferase in biliary carcinogenesis. Studies will be carried out to determine EZH2-regulated gene expression profile and its mechanism of action. The impact of EZH2 knockdown or overexpression on CCA development will be assessed in two complementary mouse models of cholangiocarcinogenesis (induced via transduction of the biliary tree and via hydrodynamic tail vein injection). The relevance of EZH2 and related signaling molecules will be validated in human CCA tissues and pre-cancerous bile duct lesions. In Specific Aim 2, we will evaluate the therapeutic efficacy of EZH2 inhibition or miR-34a replacement in conjunction with standard chemotherapy in pre-clinical models of CCA. The proposed studies will define the biological functions and molecular mechanisms of EZH2 and related signaling molecules in biliary carcinogenesis and lead to the development of new epigenetics-based target therapy.