Cdk5对垂体瘤VEGF特征性表达的调控及其在垂体瘤信号转导通路中的作用及机制研究

Pituitary tumors make up a significant number of intracranial tumors and as many as 15% of the human population. The space-occupying lesions and hormone disorder could have heavy consequences for patients about growth, development, labor ability and fertility function. Cyclin dependent kinase 5 ( Cdk5) is well known to play a pivotal role in the nervous system, VEGF is critical for the process of vasculogenesis and angiogenesis during development. Here we show the presence of specific VEGF segment in pituitary tumor. In the present study. through further investigation the differenence expression of VEGF between normal pituitary and pituitary tumor, we hope to found specific VEGF polymer or glycosylation sites, and carry on large-scale clinical screening of pituitary tumor patients for this characteristic expression of VEGF.We also focuse a great deal of attention on the role of Cdk5 in pituitary tumor. To determine whether Cdk5 may have functions in pituitary tumor through VEGF pathway, we would analyze that the relation between differenence expression of VEGF between normal pituitary and pituitary tumor to reveal the regulation mechanisms of Cdk5 in pituitary tumor and provide new potential specific biomarkers of molecular diagnosis and molecular therapy of pituitary tumor.

垂体瘤是临床最常见的神经系统肿瘤之一，约占颅内肿瘤的15%，肿瘤占位和激素分泌紊乱对于患者的生长、发育、劳动能力和生育功能等产生严重影响。细胞周期素依赖蛋白激酶5(Cdk5)是神经系统中发挥多种功能的一种重要蛋白激酶，血管内皮生长因子（VEGF）是促进肿瘤血管和内皮生长最重要的分子之一。我们在人的垂体瘤组织样本中检测到特征性的VEGF表达片段，拟通过对在垂体瘤中差异表达的VEGF蛋白的进一步研究，找到VEGF聚合体或者糖基化位点，并在大规模的垂体瘤患者中筛查此种特征性VEGF的表达，并以VEGF信号转导通路为切入点，探讨蛋白激酶Cdk5对于VEGF分泌及差异化表达的VEGF之间的相互关系，从而揭示Cdk5在垂体瘤发生发展中的调控机制，期望能从新的视角揭示垂体瘤的发病机制，为垂体瘤的分子诊断和分子治疗提供有效的分子靶点。

垂体瘤是最常见的神经系统肿瘤之一，约占颅内肿瘤的10-15%。细胞周期素依赖蛋白激酶5(Cdk5)是神经系统中发挥重要作用的一种蛋白激酶，它通过磷酸化众多的底物调节神经细胞分泌，突触可塑性，细胞凋亡等功能。我们在研究中首次发现，CDK5及其重要激活子P35表达于人的正常垂体及垂体瘤组织中，且在垂体瘤组织样本中CDK5的激活子P35的mRNA和蛋白表达明显升高，提示在垂体瘤病理过程中CDK5处于明显活化的状态。同时，我们发现血管内皮生长因子（VEGF）的表达在垂体瘤中也明显增加。在垂体瘤组织样本中我们还观察到血管内皮生长因子受体2（VEGF2）与肿瘤新生血管标志物CD31共表达。在垂体瘤细胞系GH3中抑制或敲减CDK5的表达，可以明显抑制VEGF的含量。这些结果提示CDK5可能通过影响VEGF的分泌从而参与垂体瘤的发生发展过程，CDK5抑制剂Roscovitine可能作为垂体瘤治疗的潜在靶点。