RNA结合蛋白IGF2BP1介导脊索瘤恶性生物学行为的作用及机制研究

Chordoma, a common primary malignant bone tumor with predilection to the spine column, is featured by its aggressiveness, resulting in high rate of recurrence after surgical resection. So far, there has been a paucity of evidence revealing its mechanisms of tumorigenesis and specific therapeutic targets. Currently, the RNA binding protein, IGF2BP1 has been proved to play a critical role in the development of the neural crest and the axial structure, and mediate the malignant biological behaviors of various malignancies. Besides, the receptor tyrosine kinases (RTKs) inhibitor have gained much attention due to the research of its therapeutic effects on chordoma. According to our previous data, IGF2BP1 was highly expressed in chordoma and resulted in the proliferation of chordoma. Our further data suggested it could regulate the expression of PDGFRβ, a member of RTKs and other multiple chordoma-related genes by combining to a specific mRNA sequence. Taken together, we plan to investigate the functions and mechanism of IGF2BP1 inducing the malignancy of chordoma and relevant regulative pathways in chordoma cell lines and the PDX animal model. We shall also evaluate the therapeutic efficacy of IGF2BP1-RTKs inhibitors on chordoma and underlying mechanism, thus provide laboratory evidence and a new therapeutic target for the treatment of chordoma.

脊索瘤是一种脊柱常见的原发恶性骨肿瘤，侵袭性强，术后复发率高，迄今对其发病机制了解甚少，尚无特效治疗靶点。近年研究表明RNA结合蛋白IGF2BP1在神经嵴及中轴结构发育过程中起重要作用，并介导了多种肿瘤的发展、侵袭等恶性生物学行为。另一方面，目前受体酪氨酸激酶家族（RTKs）抑制剂对脊索瘤治疗作用的探索备受关注。课题组前期实验发现脊索瘤样本中IGF2BP1呈高表达，不仅促进了脊索瘤细胞的增殖，且可通过结合特异性mRNA序列显著调控RTKs成员PDGFRβ等多种脊索瘤相关基因的表达。项目组拟从分子、细胞和脊索瘤PDX动物模型多个层面开展研究，阐明IGF2BP1介导脊索瘤恶性生物学行为的作用及上下游调控机制，探讨靶向IGF2BP1-RTKs通路抑制剂对脊索瘤的治疗效果和相关原理，为脊索瘤的治疗提供新的理论依据及药物靶点。

脊索瘤是一种中轴骨常见的原发恶性骨肿瘤，侵袭性强，术后复发率高，迄今对其发病机制了解甚少，尚无特效治疗靶点。近年研究表明RNA结合蛋白IGF2BP1在神经嵴及中轴结构发育过程中起重要作用，并介导了多种肿瘤的发展、侵袭等恶性生物学行为。另一方面，目前受体酪氨酸激酶家族（RTKs）抑制剂对脊索瘤治疗作用的探索备受关注。课题组前期实验发现脊索瘤样本中IGF2BP1呈高表达，可促进了脊索瘤细胞的增殖，且可通过结合特异性mRNA序列显著调控RTKs成员PDGFRβ等多种脊索瘤相关基因的表达。在此基础上，本项目在实施过程中根据前期设计方案，重点开展了以下研究内容并获得相应成果：（1）通过细胞、动物及临床样本多维度明确IGF2BP1对脊索瘤多种恶性生物学行为的促进作用，其中通过干预脊索瘤细胞系IGF2BP1的表达水平，发现该RNA结合蛋白可促进脊索瘤细胞的增殖、迁移、侵袭及抗凋亡，相关动物实验结果也支持了IGF2BP1在体内的促瘤作用；（2）探究了IGF2BP1相关的上下游调控信号通路，首先进一步明确了脊索瘤关键转录因子brachyury对IGF2BP1表达的调控作用及机制，后通过干预脊索瘤细胞IGF2BP1水平，探索受其调控表达并具有临床应用前景的相关靶点，其中新发现了其对PD-L1表达有调控作用，并初步明确其调控机制；(3) 利用中心临床样本，评估了IGF2B1水平作为脊索瘤预后评估指标的价值，同时进行了2代测序并进行深入分析及挖掘测序结果，对脊索瘤起源的核心机制进行了解释，并提出了脊索瘤新的分子分型。项目获得结果初步明确了RNA结合蛋白IGF2B1对脊索瘤恶性生物学行为的促进作用及上下游信号通路的调控机制，从分子层面提供了脊索瘤预后评估的新方法，优化了脊索瘤的临床决策参考指标，同时有望利用上述调控机制提升现有药物治疗效果，并开发新药物靶点。