化疗是骨肉瘤治疗的主要手段，但临床上仍有30～40％的骨肉瘤患者对化疗药物不敏感，研究表明低氧微环境可能是造成这一现象的重要原因，但机制尚未阐明。本课题组前期研究发现原代骨肉瘤样本中高表达的E3泛素连接酶WSB-1是一全新低氧诱导蛋白，在翻译后水平可调控多种目标蛋白，并在低氧微环境调控骨肉瘤化疗药物敏感性中发挥了重要作用。在此基础上，本课题将进一步明确WSB-1在骨肉瘤化疗敏感性中的作用地位，研究低氧环境对WSB-1蛋白表达的调控机制，并从分子、细胞、模型动物三个层面研究低氧诱导的WSB-1蛋白翻译后调控下游信号转导通路的作用模式，围绕WSB-1的上下游调控环节，积极探索提高骨肉瘤低氧敏感性的干预策略。通过上述研究，旨在阐明WSB-1参与调控低氧骨肉瘤化疗敏感性这一崭新的生物学功能，为骨肉瘤的药物治疗提供新的靶点，也为新型骨肉瘤治疗药物的设计提供思路。

Chemotherapy is one of the most common types for treatment of osteosarcoma, but 30～40％ of patients show poor response to chemotherapy. Accumulated evidence suggests the existence of hypoxia contributes to chemoresistance of osteosarcoma, wherever the molecular mechanism how hypoxia reduces the sensitivity of osteosarcoma to chemotherapy remains elucidated. Our preliminary data suggests that E3 ubiquitin ligase WSB-1 is induced by hypoxia and is involved in chemoresistance of osteosarcoma. In current study, we will further investigate the function of WSB-1 in chemosensitivity of osteosarcoma, the signaling pathways that involved in WSB-1 mediated chemosensitivity of osteosarcoma, and the mechanism of hypoxia induced WSB-1 expression. Furthermore, we will also try to explore the possible ways to improve the chemosensitivity of osteosarcoma. This study will not only confirm the role of WSB-1 in the chemotherapy resistance of osteosarcoma, but also provide a potential target for osteosarcoma therapy.