骨肉瘤是一种常见的原发恶性骨肿瘤，具有恶性度高、易转移、预后差的特点，目前尚缺乏明确的分子机制研究以及治疗靶点。本课题组在前期研究中发现，一种肿瘤相关蛋白磷酸酶ILKAP在骨肉瘤中存在广泛的失活突变，敲除ILKAP的转基因鼠可以自发地产生骨肉瘤。同时我们发现ILKAP可以结合并催化缺氧诱导因子HIF-1α亚基，并调节HIF-1的稳定性及转录活性，这可能是调控骨肉瘤发生的关键分子机制。本项目拟通过探索ILKAP催化HIF-1α的磷酸化位点,和催化反应完成后，HIF-1蛋白稳定性、转录活性以及对骨肉瘤细胞行为的影响，从分子和细胞水平确定ILKAP通过HIF-1调控骨肉瘤恶性生物学行为的过程；并通过转基因模型在体实验，在动物水平明确ILKAP调控HIF-1对骨肉瘤的发生、成瘤、转移的影响。本项目不仅可以为骨肉瘤病因学研究提供重要的分子机制基础，还可以为骨肉瘤的治疗提供新的理论依据及药物靶点。

Osteosarcoma is the most commonly primary malignant bone tumor, with high malignance, fast growing, early metastasis and strong invasion. There is no definite molecular target point for the cure of osteosarcoma. We found wide rate of dead-activated mutation of a tumor associated phosphatse ILKAP was exist in human osteosarcoma, and ILKAP knockout mice develop osteosarcoma automatically. We also found that ILKAP bind and de-phosphorylate HIF-1α subunit and regulate protein stability and transcription activity of HIF-1. This process may be the key mechanism of osteosarcoma generation and development. We plan to explore the specific sites about ILKAP catalytic of HIF-1α subunit, in order to clarify the mechanism about the de-phosphorylation of HIF-1α subunit. We plan to detect the change of HIF-1 protein stability, transcription activity and the effect on osteosarcoma cells after HIF-1α subunit was de-phosphorylated by ILKAP, to confirm the mechanism of ILKAP regulate HIF-1 and affect psteosarcoma generation from molecular and cellular levels. We also plan to explore the impact about ILKAP de-phosphorylat of HIF-1 in the generation and malignant behavior of human osteosarcoma with animal models. In this study we can provide the new theory of the molecular mechanism in the generation and malignant behavior of human osteosarcoma and provide now direction and medicine target point for the cure of osteosarcoma.