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。