PTEN/PI3K/AKT的持续活化在肾透明细胞癌（RCC）的恶性进展中发挥重要作用，FOXO3a基因是AKT基因的重要靶点之一。前期研究表明，FOXO3a基因的表达缺失在RCC的发生和进展中发挥重要作用，并且能够调节EMT相关基因的表达。基于前期基础及国内外进展，本课题先通过对RCC组织进行microRNA芯片检测以及生物信息学分析，筛选参与调控PTEN/PI3K/AKT/FOXO3a通路的microRNA，并假设存在PTEN/PI3K/AKT/FOXO3a/microRNA形成正反馈调控环路，使PI3K/AKT持续性活化，促进RCC的发生发展。进一步对该microRNA与PTEN/PI3K/AKT/FOXO3a通路的相互作用进行研究，通过体外细胞功能实验和裸鼠荷瘤实验验证microRNA与该信号通路所发挥的功能，分析其表达和患者临床资料的关系，为进一步寻找RCC的分子标志物提供理论依据

Sustained activation of PTEN/PI3K/AKT plays an important role in renal cell carcinoma (RCC) malignant progression. FOXO3a is one of the important targets of AKT. Previous studies showed that the deletion of FOXO3a played an important role in the tumor genesis and progression of renal cell carcinoma (RCC), and induced the expression of EMT-related genes. In this study,14 paired RCC tissues and corresponding adjacent normal tissues were detected by microRNA arrays. Combined with bioinformatics analysis, microRNAs that potentially involved in the regulation of PTEN/PI3K/AKT/FOXO3a pathway were screen out. We hypothesized that the presence of PTEN/PI3K/AKT/FOXO3a/microRNA formed a positive feedback and the persistent activation of PI3K/AKT promoted the development of RCC. Further study of the interaction between the microRNAs and PTEN/PI3K/AKT/FOXO3a pathway through in vitro and in vivo experiments will confirm the function of these microRNAs. Finally, the relationships between the expression of microRNAs and the clinical data of the patients will be analyzed.

前期研究表明，FOXO3a基因表达下调在肾癌的发生发展中均发挥了重要的调控作用。基于以上前期研究，以及microRNA芯片筛查，结合microRNA数据库分析本研究证明了mir-155在肾癌细胞系中能够靶向作用于FOXO3a基因，调控其下游的蛋白水平表达。FOXO3a基因是mir-155的靶基因之一。此外我们还发现mir-155在肾癌组织细胞中高表达。mir-155表达上调促进肾癌细胞的增殖和迁移能力。由此可见mir-155也在肾癌的发生发展中发挥了重要的调控作用，并且其可能是通过影响FOXO3a基因表达而影响肿瘤的发生发展。由于microRNA分子的特殊性，如较mRNA不易降解，较蛋白质易于检测等性质，因此mir-155具有成为肾癌潜在的分子标志可能，值得进一步研究。