SPHK1作为胶质母细胞瘤潜在治疗靶点的研究及其抑制剂筛选

Glioblastoma multiforme (GBM) is the most challenging primary malignant tumor in the central nervous system with high morbidity, mortality, and recurrence rate. Currently, its drug targets and corresponding drugs are lacking in the clinical practice. Therefore, it is urgent to develop drug targets and corresponding drugs for GBM. Our bioinformatics analyses and experimental data showed that the elevated level of SPHK1 was observed in GBM patients, which was strongly correlated with poor prognosis and reduced overall survival; overexpression of SPHK1 also promoted the tumor cell invasion, metastasis, and clone formation. Using virtual screening, we preliminary screened out five small molecules whose scores were higher than the natural ligand of SPHK1. Based on these results, we propose SPHK1 as a potential therapeutic target of GBM and the application of its inhibitors could be effective drugs for the treatment of GBM. In this study, we will investigate the functions, mechanisms and methylation regulation of SPHK1 to confirm that it is a potential therapeutic target of GBM. Furthermore, we will identify inhibitors targeting SPHK1 using virtual screening followed by high throughput drug screening. It is necessary and important to identify SPHK1 as a potential drug target and guide the treatment of GBM.

胶质母细胞瘤（GBM）是神经系统发病率、复发率和死亡率最高的原发性恶性肿瘤。目前临床上缺乏GBM的治疗靶点，亦缺乏相应的靶向药物。因此，对GBM治疗靶点及相应靶向药物的发现迫在眉睫。我们的生物信息学分析和实验数据显示SPHK1在GBM中高表达，并与患者的预后不良和低生存率密切相关；过表达SPHK1可以增加肿瘤细胞侵袭、转移和克隆形成。我们初步以SPHK1为靶点虚拟筛选出了5个得分值大于其天然配体的化合物。我们认为SPHK1是GBM潜在治疗靶点，其抑制剂是治疗GBM的有效药物。本研究将从SPHK1的功能、作用机制和甲基化表达调控三个方面确认SPHK1为GBM潜在治疗靶点。并采用虚拟筛选结合高通量筛选模型筛选效力高、特异性强的SPHK1抑制剂。本课题的研究对确立SPHK1为GBM药物靶点及GBM的临床治疗具有重要的指导意义。

胶质母细胞瘤（GBM）是神经系统发病率、复发率和死亡率最高的原发性恶性肿瘤。目前临床上缺乏GBM的治疗靶点，亦缺乏相应的靶向药物。因此，对GBM治疗靶点及相应靶向药物的发现迫在眉睫。我们的研究发现SPHK1在GBM中高表达，并与患者的预后不良和低生存率密切相关；过表达SPHK1可以增加肿瘤细胞增殖、侵袭、转移和克隆形成。小鼠异种移植瘤实验结果表明，过表达SPHK1可以促进胶质瘤的生长，而敲低SPHK1能够抑制胶质瘤的生长。U251细胞过表达SPHK1转录组实验结果表明过表达SPHK1后差异基因主要富集在炎症相关信号通路，表明SPHK1可能通过发挥抗炎作用来发挥抗胶质瘤作用。进一步研究显示，过表达SPHK1可以增加PTX3的表达，并且过表达SPHK1可以补救敲低PTX3对PTX3蛋白表达的影响，提示PTX3受SPHK1的调控。随后生物信息学分析发现转录因子ATF3与SPHK1和PTX3均具有高度相关性，并且PTX3启动子区有ATF3的结合位点，过表达SPHK1亦可以增加ATF3的表达，提示SPHK1可能通过增加转录因子ATF3的表达进而增加PTX3的表达。最后，我们对SPHK1的抑制剂进行了筛选，通过筛选得到了5个活性大于天然配体的化合物。通过以上研究我们明确了SPHK1可以作为胶质母细胞瘤的潜在药物靶点，其抑制剂有希望开发为临床上治疗胶质瘤的潜在药物。