Epigenetic Mechanisms of Biliary Epithelial Neoplasia

项目描述 胆管癌（CCA）是一种高度恶性的上皮癌， 胆管树CCA的发病率和死亡率在世界范围内不断上升，目前 没有有效的化学预防或治疗。的分子发病机制 潜在的胆管上皮瘤变涉及遗传和表观遗传变化 导致致癌和肿瘤抑制途径的改变。而 最近的高通量下一代测序分析有助于 鉴定CCA中的遗传异常，表观遗传学的潜在影响 对胆管上皮瘤变的影响仍然很大程度上未知。 目前的建议是基于我们令人兴奋的初步研究， EZH 2是一种关键的组蛋白甲基转移酶， 通过H3 K27三甲基化在胆管中表达肿瘤抑制因子miR-34 a 癌细胞，并且miR-34 a通过靶向Notch 1抑制CCA细胞生长， Notch 2和Jagged 1。我们的实验结果支持这一假设， EZH 2组蛋白甲基转移酶促进胆管癌的发生 miR-34 a的表观遗传沉默和随后的Notch信号传导的激活， 并且EZH 2抑制或miR-34 a替代疗法与 标准的化疗方案可能代表了一种有效的策略， 治疗人类CCA。这些假设将在两个评估 互补的具体目标。在具体目标1中，我们将评估效果， EZH 2组蛋白甲基转移酶在胆管癌发生中的作用机制 将进行研究以确定EZH 2调节的基因表达谱 及其作用机制。EZH 2敲低或过表达的影响 将在两种互补的小鼠模型中评估CCA发育， 胆管癌发生（通过胆管树的转导和通过 流体动力学尾静脉注射）。EZH 2和相关信号的相关性 分子将在人类CCA组织和癌前胆管中得到验证 病变在具体目标2中，我们将评估EZH 2的治疗效果 抑制或miR-34 a替代与标准化疗联合治疗 CCA的临床前模型。拟议的研究将确定生物学 EZH 2及其相关信号分子在乳腺癌中的功能和分子机制 胆管癌的发生，并导致发展新的表观遗传学为基础的 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.