Polo样激酶2在抑制胶质瘤细胞增殖及血管生成中的作用及机制研究

The tumor cell proliferation and angiogenesis is the important mechanism for the growth of glioma. In our previous study, we analyzed the transcriptome sequencing in 6 cases of malignant gliomas and 6 cases of normal brain tissue, and found that, the expression of Polo like kinase 2 is significant low. Further, according to the analysis of the TCGA database, we found that the lower expression of PLK2, the worse of the prognosis. Then with the Gene Set Enrichment Analysis, we found that the JAK-STAT and VEGF pathway was activated obviously, but the apoptosis pathway was significantly inhibited , and these pathways are the important pathway in cell proliferation and angiogenesis of glioma. Therefore, in the present study, we firstly verify the the relationship between the expression of PLK2 in gliomas and with the clinical features and prognosis of patients with gliomas. And then, detected the effect of PLK2 on tumor cell proliferation, cell cycle, apoptosis and angiogenesis in vivo and in vitro. Finally, we will try to screen and identify the potential downstream target molecule of PLK2, and preliminarily expounds mechanism of plk2 in glioma.

肿瘤细胞增殖及血管生成是胶质瘤生长的重要机制。本课题组前期通过对6例恶性胶质瘤和6例正常脑组织进行转录组测序分析，发现Polo样激酶2显著低表达。进一步通过TCGA数据库分析发现PLK2的表达量越低预后越差。而后通过基因集富集分析方法发现JAK-STAT、VEGF等通路明显激活，而显著抑制凋亡（APOPTOSIS）通路，而上述几个通路是胶质瘤细胞增殖与血管生成的重要通路。因此本实验首先拟验证PLK2在胶质瘤中的表达及与胶质瘤患者临床特征及预后的关系。而后行体内外实验确定PLK2对胶质瘤细胞增殖、周期、凋亡和血管生成的影响，最后从基因和蛋白层面筛选鉴定PLK2潜在的下游靶分子，初步阐述PLK2在胶质瘤中的作用机制。

在GBM患者中PLK2的表达降低，这可能受其DNA甲基化的调节。此外，PLK2低表达与较好的预后相关，强调其作为预后生物标志物的潜力。通过单因素和多因素分析，PLK2可能是GBM的独立预后因素。因此，PLK2可作为GBM预后良好的独立生物标志物。PLK2的表达随着胶质瘤的恶性程度逐渐增加。PLK2高表达与胶质瘤预后不良相关。以PLK2为靶点的短发夹rna（shPLK2）在体内外均能抑制胶质瘤细胞的存活并诱导其凋亡。环指蛋白180（RNF180）是一种E3泛素连接酶，与PLK2相互作用，诱导PLK2泛素化。胶质瘤细胞中PLK2的过度表达显著抑制RNF180上调诱导的细胞凋亡。随着胶质瘤恶性程度的加重，RNF180的表达水平逐渐降低。