YB-1介导血管内皮细胞凋亡的分子机制研究

以血管内皮细胞（VEC）增殖、迁移为基础的血管新生对肿瘤的发生发展具有重要作用。抑制VEC增殖并诱导其凋亡是抑制新生血管形成的关键。尽管多种因素均可影响VEC增殖和凋亡的进程，然而在肿瘤血管新生过程中，调节VEC增殖和凋亡基因表达的分子机制目前仍不清楚。我们前期研究发现，转录因子Y盒结合蛋白1 （YB-1）CTD结构域可通过上调VEC中凋亡基因caspase3表达和活化而诱导VEC凋亡，提示YB-1具有抑制血管新生的功能。基于此，本课题探讨YB-1诱导VEC凋亡与其对凋亡基因表达调节之间的关系，鉴定YB-1 CTD介导凋亡基因表达所依赖的转录调节因子并探明其相互作用的分子机制；用移植瘤动物模型探讨YB-1 CTD对肿瘤血管新生的影响，研究YB-1 CTD抗肿瘤血管新生的作用机理。本研究为人们对YB-1蛋白功能的认识提供新的实验依据，为VEC凋亡调控研究和抗肿瘤血管新生药物研发提供新的线索。

Abnormal proliferation and migration of vascular endothelial cells (VECs) during angiogenesis play an important role in tumor occurrence and development. Inhibiting proliferation and inducing apoptosis of VECs are critical for controlling tumor angiogenesis. Although many factors can affect the apoptosis process of VECs, the molecular mechanism of apoptosis gene transcription regulation during tumor angiogenesis remains unknown. In previous studys, we found that Y-box binding protein 1 (YB-1) upregulates caspase3 expression and activation and induces VEC apoptosis via C-terminal domain (CTD), which suggested potential roles of YB-1 in suppressing tumor angiogenesis. Therefore, the aims of the present study were to investigate the relationship of YB-1 in regulating VEC apoptosis and apoptosis-related genes expression, and to reveal YB-1 CTD dependent transcriptional co-factors in regulating apoptosis-related gene transcription. Furthermore, cell cocultivation and transplantation tumor animal models were used to observe the influences of YB-1 CTD on angiogenesis and reveal the molecular mechanisms of YB-1 CTD in suppressing tumor angiogenesis. This study will describe a novel insight into the regulation of GC box-related genes transcripted by YB-1 and provide new understandings of VEC apoptosis regulation and tumor angiogenesis suppression.