SVIP及雄激素受体与神经胶质瘤的相关性及机制研究

Patients with glioblastoma have high mortality rates, very poor prognosis and easily have relapse. Till now, the mechanism causing glioblastoma is still unkonw. We found that the grade of the tumor was closely related to the protein level of SVIP and SVIP knockdown by RNAi method could result in down-regulation of p53 protein level. Beside that, SVIP was proved to be regulated by androgen receptor (AR) at the transcriptional level. Therefore, we can deduce from those findings that AR-SVIP-p53 pathway and the serum testosterone level of the patients may play significant roles in glioma progression. To confirm the hypothesis, the research should be in progress as below: 1) observing the cell proliferation ability regulated by SVIP, and to prove the change of cell proliferation ability is p53wt dependent; 2) analyzing the relationship between glioma and AR/SVIP/p53/ testosterone with clinical specimens respectively; 3) proving SVIP is regulated by AR level at the transcriptional level, and to identify the androgen reactive elements (ARE) in promoter region of SVIP gene; 4) elucidating the mechanism that SVIP regulates p53wt at the post-translational level; 5) observing the effect of testosterone level on tumor progression with animal model. This research should be very important to illuminate the nature of occurrence and development of glioblatoma, and to monitor the condition of patients after clinical surgery, furthermore, it also present a new target for glioma treatment.

神经胶质瘤死亡率高、易复发、预后差，目前病理机制仍不明确。我们发现一种小的VCP/P97相互作用蛋白（SVIP）表达水平与胶质瘤分期密切相关。另外，SVIP影响p53wt的蛋白水平，同时它还受到雄激素受体（AR）的调节。故推测AR-SVIP-p53通路在胶质瘤发生发展过程中起了重要作用。为了证实上述假设，我们拟开展如下研究：1）临床样本分析AR、SVIP和p53表达水平及睾酮水平与胶质瘤的关系；2）观察SVIP对不同细胞系细胞增殖的影响，证实这种影响是p53wt依赖的；3）证实AR在转录水平上抑制SVIP表达的机制，找到SVIP启动子区域的雄激素受体反应元件；4）探索SVIP在蛋白水平上调节p53wt的机制；5）用实验动物模型证实睾酮水平影响胶质瘤的生长速度及宿主的生存时间。这一研究对阐明胶质瘤发生发展的规律意义重大，为胶质瘤病人术后监测提供了新思路，为胶质瘤的治疗提供了新的靶点。

神经胶质瘤死亡率高、易复发、预后差，目前病理机制仍不明确，且目前没有有效的靶向治疗药物。我们发现一种小的VCP/P97相互作用蛋白（SVIP）表达水平、雄激素受体（AR）以及血清睾酮水平与胶质瘤分期密切相关，推测AR-SVIP-p53通路在胶质瘤发生发展过程中起了重要作用。为了证实上述假设，我们开展了如下研究：1）观察SVIP对不同细胞系细胞增殖的影响， siSVIP导致p53wt细胞系增殖加快，而对p53突变型胶质瘤细胞系没有影响，这暗示SVIP抑制细胞增殖与p53的基因型有关；2）临床样本分析AR、SVIP表达水平及睾酮水平与胶质瘤的关系，免疫印迹、免疫组化和RT-PCR结果显示随着胶质瘤级别升高，AR表达在蛋白和核酸水平上均有明显增加，而SVIP表达水平随级别升高而降低，临床样本也显示胶质瘤病人的血清睾酮水平高于正常人，女性患者尤其明显；3）证实AR在转录水平上抑制SVIP表达，随着睾酮水平升高，AR表达增加，SVIP表达下调明显；4）参考目前前列腺癌药物治疗的方式及发展趋势，结合胶质瘤的特殊性，我们证实雄激素拮抗药物对胶质瘤的生长的抑制作用，在细胞水平上雄激素拮抗药物MDV3100可以抑制U87细胞增殖，而雄激素拮抗药物MDV3100与ARN509均不影响U251细胞系增殖，动物实验显示MDV3100能很好的抑制裸鼠皮下U87形成的肿瘤的生长。提示我们雄激素截抗药物治疗胶质瘤的可行性，以及胶质瘤治疗过程需要区分p53基因型。研究计划基本完成，这一研究阐明AR-SVIP-p53在胶质瘤发生发展过程中意义重大，为胶质瘤的治疗提供了三个新的靶点，为胶质瘤的药物治疗新思路及治疗依据。