PRAS40在尤文肉瘤发生发展中的作用和分子机制研究

项目名称： PRAS40在尤文肉瘤发生发展中的作用和分子机制研究

项目编号： No.81201562

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 黄琳

作者单位： 大连医科大学

项目金额： 23万元

中文摘要： 尤文肉瘤是一种恶性度高，极易转移的肿瘤，具有染色体易位，导致EWS基因与ETS转录因子家族形成融合蛋白EWS/ETS。但是融合蛋白并不能独自引起尤文肉瘤形成。申请人发现在尤文肉瘤细胞中PRAS40蛋白表达增强，基因敲除PRAS40显著抑制细胞增殖，迁移和侵袭，同时caspase3活化型水平增高。因前期研究结果显示基因敲除PRAS40后Akt磷酸化水平降低，所以我们推测PRAS40在尤文肉瘤细胞中可能通过正反馈来参与Akt活性的调节，进而抑制凋亡，促进细胞增殖，迁移和侵袭。为弄清PRAS40在尤文肉瘤细胞中致癌作用的机制，本项目拟通过进一步调查基因敲除PRAS40对尤文肉瘤细胞的凋亡和Akt上游因子活性的影响，弄清PRAS40调节Akt活性的机理。并应用蛋白质组学的方法来全面筛选并确定在尤文肉瘤细胞中与PRAS40相互作用的因子，从而揭示PRAS40的致癌机制，有望为新药开发提供新靶点。

中文关键词： PRAS40；尤文肉瘤；凋亡；胰岛素受体；信号转导

英文摘要： Ewing's sarcoma is a highly aggressive and highly metastatic tumor predominantly afflicting adolescents and young adults. With conventional treatment, the 5-year disease-free survival rate for patients with localized Ewing's sarcoma is only 60-70% and that for individuals with metastases drops to less than 20%. Thus, novel treatments are needed urgently. EWS encodes an RNA-binding protein whose function remains largely unknown, whereas the chromosomal translocations, which fuse the N-terminal domain of EWS to the DNA-binding domain of the ETS family transcription factors including FLI-1, are thought to be responsible for causing Ewing's sarcoma. However, the ectopic expression of EWS/FLI-1 by itself is insufficient for carcinogenesis, suggesting that additional events are required. We have reported that the proline-rich Akt substrate of 40 kDa (PRAS40) is an EWS target gene and contributes to the carcinogenesis of Ewing's sarcoma. The expression of PRAS40 protein is increased in Ewing's sarcoma cells and the knockdown of PRAS40 significantly repressed the proliferation, migration and invasion of Ewing's sarcoma cells. The knockdown of PRAS40 was found to induce apoptosis in melanoma cells. The introduction of PRAS40 in mouse brain protects neuronal cells from apoptosis, and the phosphorylation of PRAS40 at Thr2

英文关键词： PRAS40；Ewing's sarcoma；apoptosis；insulin receptor；signal transduction