microRNA-223通过IKKα调控NF-κB信号通路导致慢性淋巴细胞白血病耐药的机制研究

项目名称： microRNA-223通过IKKα调控NF-κB信号通路导致慢性淋巴细胞白血病耐药的机制研究

项目编号： No.81470336

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 周可树

作者单位： 郑州大学

项目金额： 70万元

中文摘要： 慢性淋巴细胞白血病（CLL）目前仍是一种不可治愈的疾病，肿瘤细胞发生耐药是导致患者死亡的主要原因。microRNA(miRNA)表达紊乱和 NF-κB信号通路异常活化是CLL耐药的重要因素。我们前期研究显示miRNA-223在CLL中显著低表达，难治耐药患者中表达更低，为CLL独立不良预后因素；同时发现 NF-κB信号通路活化蛋白 IKKα在CLL中特别是难治耐药患者表达明显升高。初步功能研究显示miRNA-223可能通过靶向IKKα而异常活化NF-κB信号通路导致CLL细胞耐药。本课题拟在细胞系、动物体内及CLL患者原代细胞三个层面进一步验证miRNA-223 ①参与CLL耐药；②直接调控 IKKα；③通过调控IKKα异常活化NF-κB信号通路参与CLL耐药，从而明确miRNA-223在CLL耐药中的具体作用机制，阐明CLL潜在的耐药原因，为其治疗提供新靶点，具有重要的理论和实际意义。

中文关键词： 慢性淋巴细胞白血病；微小RNA；NF-κB信号通路

英文摘要： Chronic lymphocytic leukemia (CLL) is still an incurable disease, drug resistance of tumor cells is the main reason results in patient death. CLL　had the abnormal expression of microRNA (miRNA) and continuous activation of NF-κB signaling pathway which contributed to the drug resistance.Our previous studies show that exprssion of miRNA-223 was significantly low in CLL, especially in the relapsed/refractory CLL patients and was an independent adverse prognostic factor. Simultaneously we also found IKKα ,which was an important activator of non-canonical NF-κB signaling pathway , was high expressed in CLL and was negatively correlated with the low expression of miRNA-223.Our preliminary functional study showed that IKKα might be the target of miRNA-223 in CLL.All these datas indicate that miRNA-223 might contribute to the drug resistance of CLL through activating NF-κB signaling pathway by targeting IKKα .So we design this project to identify ① low exprssion of miRNA-223 will lead to the drug resistance of CLL,② miRNA-223 target IKKα directly,③ miRNA-223 contributes to the drug resistance of CLL through activating NF-κB signaling pathway by targeting IKKα. We will identify the above outcomes in cell lines, NOD/SCID mouse model and the primary CLL cells. This project will elucidate the exact mechanism of miRNA-223 in CLL drug resistance, explain the possible reason of drug resistance in CLL, and provide a new therapeutic target for the treatment. So this project has great academic and applicative value.

英文关键词： chronic lymphocytic leukemia;microRNA;NF-κB signaling pathway