缺氧诱导因子HIF-1alpha在人骨肉瘤多药耐药机制中的作用研究

项目名称： 缺氧诱导因子HIF-1alpha在人骨肉瘤多药耐药机制中的作用研究

项目编号： No.81201633

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 马琼

作者单位： 中国人民解放军第四军医大学

项目金额： 23万元

中文摘要： 肿瘤细胞产生多药耐药（MDR）是目前骨肉瘤细胞逃避化疗药物攻击的最重要的细胞防御机制，也是临床骨肉瘤联合化疗失败最常见又最难解决的一个问题。肿瘤细胞产生耐药性是一个多靶点、多步骤、多因素参与的过程，机制复杂，有多种细胞因子、蛋白酶类和调控基因的参与。本课题组前期研究证明，缺氧诱导因子HIF-1a 与骨肉瘤多药耐药密切相关，可能在其产生过程中发挥了极其重要的作用。本研究拟在明确HIF-1a 的表达分布与骨肉瘤细胞多药耐药相互关系的基础上，利用体外缺氧模型研究HIF-1a 参与骨肉瘤细胞多药耐药的作用机制。进一步通过小鼠体内试验证实HIF-1a 或其调控的下游基因表达受到抑制的小鼠是否重新恢复了对多种骨肉瘤化疗药物的敏感性。通过本课题对HIF-1a 功能及其下游调控基因的深入研究将有助于进一步阐明骨肉瘤多药耐药的生成机理，为骨肉瘤的临床治疗提供新的思路和实验依据。

中文关键词： 骨肉瘤；多药耐药；HIF-1α；SKA1；

英文摘要： So far multidrug resistance is the most important mechanism of osteosarcoma cells escaping from chemotherapeutics, also the most common and difficult problem of failed combination chemotherapy dealing with osteosarcoma clinically.Tumor cells developing drug resistance is a multi-target,multi-step and multi-factor involved procedure. Its mechanism is complicated, involving several cytokines,protease,and regulating genes.Our previous studies demonstrate that hypoxia inducible factor HIF-1a is closely related with multi-drug resistance of osteosarcoma, and probably plays an important role in it.This project intends to find out the relationship between expression,distribution of HIF-1a and multidrug resistance of osteosarcoma, on that basis we will examin the mechanism of HIF-1a involed in multidurg resistance of osteosarcoma by in vitro hypoxia cell model.Mice with HIF-1a or its downsteam genes inhibited will be used to testify whether tumor cells become sensitive to drugs or not.This project will uncover the mechanism of multidrug resistance of osteosarcoma further, and supply a new way of clinical therapy on osteosarcoma and as well as experimental basis.

英文关键词： osteosarcoma；multidrug resistance；HIF-1α；SKA1；