新胰腺癌促癌基因CNTD2调控胰腺癌细胞恶性增殖的作用及机制研究

项目名称： 新胰腺癌促癌基因CNTD2调控胰腺癌细胞恶性增殖的作用及机制研究

项目编号： No.81502054

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 宋彬

作者单位： 中国人民解放军第二军医大学

项目金额： 18万元

中文摘要： 胰腺癌恶性程度高，对人类健康危害巨大，目前胰腺癌发病机制仍未阐明，缺乏有效治疗靶点，其分子病理机制亟待深入研究。本课题组前期通过网络数据库和生物信息学方法筛选出一个新型胰腺癌促癌基因CNTD2，小样本回顾分析发现其高表达与患者不良预后显著相关；体外过表达CNTD2能显著促进胰腺癌细胞周期进展并上调c-Myc表达，提示CNTD2可能通过调控c-Myc的机制促进胰腺癌进展。本项目拟通过构建过表达及沉默表达胰腺癌细胞系，在体内外观察CNTD2对胰腺癌细胞恶性表型的调控作用；并采用表达谱芯片检测、共表达网络分析和染色体共沉淀等实验方法阐明其分子机制；利用裸鼠荷瘤模型，初步评价靶向干预CNTD2的治疗意义；最后通过分析临床大样本中CNTD2表达水平与胰腺癌患者临床指标、治疗应答及预后相关性进一步明确其临床应用价值。对CNTD2的功能研究将有助于揭示胰腺癌发生发展的分子机理，为胰腺癌诊疗提供潜在靶点。

中文关键词： 胰腺癌；CNTD2；c-Myc；增殖；机制

英文摘要： Pancreatic ductal adenocarcinoma (PDAC) is an almost universally lethal disease which represents a major challenge to human health, however, the mechanisms involved in the oncogenesis of PDAC remained elusive and the effective therapy targets have not been identified. By informatics analysis of online databases, we initially identified a potentially new oncogene, Cyclin N-terminal Domain containing 2 (CNTD2), in PDAC. Retrospective analysis of a small cohort of PDAC sample demonstrated that the high level of CNTD2 expression is closely correlated with the poor prognosis of PDAC patients; moreover, forced overexpression promoted cell cycle progression in PDAC cells by upregulating c-Myc expression, indicating that CNTD2 could potentiate the development of PDAC possibly by controlling c-Myc expression. In this study, we are planning to figure out the effect of CNTD2 expression on malignant behaviors of PDAC cells by overexpression and knowckdown experiments; furthermore, molecular mechanisms by which CNTD2 promotes the tumorigenesis of PDAC will be explored by using mRNA expression microarrays, coexpression net analysis, and ChiP assays; in addition, xenograph tumor models in nude mice will be exploited to evaluate the potential of targeting CNTD2 in treating PDAC; finally, we will clearly define the clinical significance of CNTD2 expression in PDAC by analyzing the correlations among CNTD2 expression, other clinical parameters, therapeutic response and prognosis of patients in a large amount of clinical cancer samples. We believe that this study would elucidate the functions of CNTD2, contributing to deepen our understanding of molecular mechanisms of PDAC oncogenesis and providing a potential target for diagnosis and treatment of PDAC.

英文关键词： pancreatic cancer;CNTD2;c-Myc;proliferation;mechanisms