Hippo/YAP信号通路在骨肉瘤耐药过程中的功能和机制的研究

项目名称： Hippo/YAP信号通路在骨肉瘤耐药过程中的功能和机制的研究

项目编号： No.81472513

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： 毕文志

作者单位： 中国人民解放军总医院

项目金额： 72万元

中文摘要： 骨肉瘤是骨科最主要的恶性肿瘤，致死致畸率极高，化疗耐药是骨肉瘤治疗效果不佳的主要原因。我们和其他已报道Hippo/YAP信号通路在很多肿瘤上发现存在过表达和激活，且参与多种肿瘤的耐药（Oncogene，2013），但其在骨肉瘤耐药过程中的功能和机制尚不明确。我们前期的工作基础表明Hippo/YAP信号通路的核心蛋白YAP在耐药型骨肉瘤标本上呈现过表达，细胞上过表达或敲低明显影响抗肿瘤药物顺铂诱导骨肉瘤细胞的凋亡。基于此，我们拟采用细胞生物学技术和信号转导研究的手段，结合细胞和动物模型以及临床骨肉瘤标本，对Hippo/YAP信号通路在骨肉瘤耐药发生中的作用进行深入的研究,鉴定和筛选Hippo/YAP通路在骨肉瘤耐药发生过程中调控的关键下游基因，并对其功能和机理在体内和体外的进行验证，旨在阐明Hippo/YAP信号通路在骨肉瘤耐药产生中的作用和分子机制,为临床骨肉瘤的药物治疗提供理论依据。

中文关键词： 骨肉瘤；耐药性；Hippo；YAP；信号传导

英文摘要： Drug resistance and metastasis are the two most important mechanisms responsible for the failure of current therapeutic treatments in osteosarcoma. We and others had reported that Hippo/YAP signaling pathway is over-expressed and activated in a serial of different type tumors and it has been also shown highly related with drug resistance in several kinds of tumors (Oncogene, 2013). However, it remains largely unknown whether the activation of Hippo/YAP signaling pathway contributes to the drug resistance of osteosarcoma. Our primary data indicated that YAP is over-expressed in the clinic drug-resistant osteosarcoma specimens. Both overexpression and knockdown of YAP interfere with the apoptosis of osteosarcoma cells induced by Cisplatin (CDDP) treatment. Based on these observations, we plan to further determine the function of Hippo/YAP signaling pathway in drug resistance of osteosarcoma both in cell lines and clinical specimens, to identify the key target genes involved in Hippo/YAP signaling pathway underlying the drug resistance of osteosarcoma. Finally, we also aim to elucidate the function and molecular mechanisms of Hippo/YAP signaling in drug resistance of osteosarcoma both in vitro and in vivo. In summary, we plan to explore the molecular mechanism underlying drug resistance of osteosarcoma with the implication of a noval theraputic avenue for osteosarcoma treatment.

英文关键词： osteosarcoma;drug resistance;Hippo;YAP;signal transduction