骨肉瘤中miR-205的表观沉默机制研究及其YAP1相关调控机制研究

项目名称： 骨肉瘤中miR-205的表观沉默机制研究及其YAP1相关调控机制研究

项目编号： No.81502328

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 吴大江

作者单位： 中国人民解放军第二军医大学

项目金额： 16万元

中文摘要： 骨肉瘤是青少年最常见的原发性恶性肿瘤，预后差。骨肉瘤中的microRNA研究对于肿瘤机制研究、早期诊断和预后评价均有重要意义。我们前期的芯片筛选发现，miR-205在骨肉瘤组织中出现显著的转录抑制，而且5-AZA和TSA处理可以导致miR-205上调，提示miR-205可能受到表观沉默机制调控。同时还发现miR-205预测靶向YAP1，且二者表达呈负相关。因此，本项目拟进行两个方面机制研究：首先通过miR-205启动子区DNA甲基化、组蛋白乙酰化修饰水平分析来研究miR-205的下调机制；随后验证miR-205能否靶向调控Hippo通路中的癌基因YAP1，从而抑制骨肉瘤增殖和侵袭能力。最终在动物模型和临床骨肉瘤样本中验证miR-205下调的表观调控机制及miR-205通过Hippo/YAP1相关通路调控骨肉瘤增殖和侵袭的机制，从而为骨肉瘤的早期诊断，预后评价等领域提出新的研究靶点和参考。

中文关键词： 骨肉瘤

英文摘要： Osteosarcoma is the most common malignancy in adolescent with a poor prognosis. Studies regarding the microRNA in osteosarcoma is of great importance for the pathogenesis, early diagnosis and prognostic assessment. Our previous microarray chips revealed a significant transcription repression of miR-205 in osteosarcoma, and a treatment of 5-AZA and TSA could up-regulate the expression of miR-205. Both finding indicated that miR-205 may have been regulated by epigenetic silencing mechanisms. We also noticed that miR-205 was predictive of and negatively associated with YAP1. Therefore, we planned to carry out the study in the following two parts: firstly, the analysis of DNA methylation of promoter in miR-205 together with the histone acetylation level will be performed to study the down-regulation mechanism of miR-205; secondly, the targeted regulation of oncogene YAP1 in the Hippo pathway and its successive effect of inhibiting proliferation and invasion of osteosarcoma will be further determined. Finally, the epigenetic mechanism of miR-205 down-regulation and inhibition of proliferation and invasion of osteosarcoma via Hippo/YAP1 pathway will be verified in both clinical sample and animal model. We hope to bring a new target for the early diagnosis and prognostic assessment of osteosarcoma.

英文关键词： osteosarcoma