Pokemon上调linc01451诱导膀胱肿瘤细胞上皮-间质转化及肿瘤干细胞转化的机制研究

Our previous study have demonstrated that pokemon plays an important role in the tumorigenesis, development and tumor metastasis in bladder cancer. We then found the expression levels of linc01451 and pokemon in bladder cancer were significantly positive correlated through querying the GEO, TCGA database and related data analysis. Further depth data analysis showed that Pokemon may affect TGF-β signaling pathway by regulating the expression of linc01451. Previous experiment have preliminarily confirmed that pokemon regulate the expression of linc01451, and the change of linc01451 expression influence the expression of downstream smad3 and smad6, further change bladder cancer stem cells and epithelial-mesenchymal transition resulting in drug resistance in bladder cancer. But the specific mechanism is still unclear. Therefore, we will explore the mechanism of pokemon regulate linc01451 and linc01451 regulate TGF-β signaling pathway in vivo and in vitro by using RNA interference, overexpression, ChIP, RNA pull down and luciferase assays, to provide new strategies for the therapy of bladder cancer.

我们前期研究发现Pokemon在膀胱癌的发生和发展及肿瘤的转移中扮演重要角色。通过查询GEO、TCGA数据库及相关数据分析，我们发现linc01451与Pokemon在膀胱癌中的表达呈明显的正相关。进一步深度数据分析显示Pokemon可能通过调控linc01451的表达进而影响TGF-β信号通路。前期实验已初步证实Pokemon调控linc01451的表达，且linc01451的改变影响下游的Smad3和smad6的表达，并进一步改变膀胱癌肿瘤干细胞及膀胱癌上皮-间质转化从而使膀胱癌发生药物抵抗，但具体作用机制仍然不清楚。因此，本项目拟通过RNA干扰、过表达、ChIP以及RNA pull down，luciferase等实验手段从体内和体外水平多方面研究Pokemon调控linc01451的机制及linc01451调控TGF-β信号通路的机制，为膀胱癌的治疗提供新的策略。

促癌基因Pokemon在膀胱癌的发生和发展及肿瘤的转移中扮演重要角色。前期的生物信息学研究提示，Pokemon可能通过调控非编码RNA Linc01451的表达，进而影响膀胱癌细胞上皮-间质转化及肿瘤干细胞转化的生物学行为，且linc01451的改变可能影响下游的Smad3和smad6的表达，并进一步改变膀胱癌肿瘤干细胞及膀胱癌上皮-间质转化从而使膀胱癌发生药物抵抗，但具体作用机制仍然不清楚。因此，本项目拟通过RNA干扰、过表达、ChIP以及RNA pull down，luciferase等实验手段从体内和体外水平多方面研究Pokemon调控linc01451的机制及linc01451调控TGF-β信号通路的机制。本课题发现，Linc01451在膀胱癌组织中的表达水平明显高于正常组织，而且Linc014511可以直接与LIN28A和LIN28B结合，通过激活TGF-β/Smad信号通路促进上皮间质转化，进而加重膀胱癌进展。