脊索瘤是一种常见脊柱原发恶性骨肿瘤，临床仅以手术切除为主，对放疗不敏感，缺乏有效的药物治疗，术后易复发且预后差。因此，从分子水平探讨与脊索瘤发生和复发有关的信号通路和寻找有针对性的药物对其防治具有重要意义。作为能够调控多种细胞生物学过程的关键通路，蛋白酶体信号通路日益受到关注。本课题组在前期实验中发现，与正常脊索组织比较，原发和复发的脊索瘤组织表达更高的泛素-蛋白酶体途径的REGγ以及HDM2，而p53水平则下调（脊索瘤中为野生型p53）。 我们在同样含野生型p53的A549细胞中发现REGγ-HDM2-p53通路及其作为反馈调节环路对肿瘤增殖、凋亡的调控具有显著作用，但该通路如何影响脊索瘤的发生和复发尚不明确。基于此，我们将利用细胞和动物模型深入研究该信号通路及其阻断剂Nutlin-3在脊索瘤发生和复发中的作用，为进一步明确脊索瘤发生和复发的分子机制和新靶点药物的开发应用提供实验基础。

Chordoma is one of the common primary malignant tumors of the spine. Currently, the surgical resection is the only potential curable strategy for the management of chordoma. It has a high rate of local recurrence due to low sensitivity to radiotherapy and chemotherapy. The outcome and prognosis is poor. Therefore, it is very important to study the relevant signal pathway which is associated with the development and recurrence of chordoma, and try to develop new target drugs to improve the prognosis of chordoma. As we know, proteasome pathway is associated with many cytobiological processes. According to our previous research, we found that there were higher expression of REGγ and HDM2 and lower expression of p53 (wild-type in chordoma) in the primary and recurrent chordoma than those in notochord. We also found that REGγ-HDM2-p53 pathway is a feedback loop and plays a significant role in the proliferation and apoptosis in A549 cell line with wild-type p53. However, the effect of REGγ-HDM2-p53 feedback loop in the recurrence of chordoma is still unknown. As a result, our study will focus on the REGγ-HDM2-p53 pathway and its inhibitor Nutlin-3 in cell lines and animal models of chordoma. We aim to clarify the molecular mechanisms of chordoma development and recurrence in hope to provide the experimental basis for developing new target drugs.