USP9x去泛素化β-catenin促进肺癌细胞TRAIL耐受的机制研究

抑制型受体OPG、DcR1与DcR2与肿瘤细胞发生TRAIL耐受密切相关，但其表达调控的机制尚不明确。我们前期实验发现：USP9X可以通过去泛素化稳定β-catenin的水平，β-catenin能调控抑制型受体OPG、DcR1与DcR2的转录表达。因此，本项目拟以肺癌为研究对象，首先检测肺癌组织中USP9X/β-catenin与抑制型受体OPG、DcR1、DcR2表达的相关性；其次探讨核内β-catenin/TCF/LEF转录复合体对抑制型受体表达的影响；再从蛋白质去泛素化修饰水平研究USP9X稳定β-catenin并促其入核，以深入阐释β-catenin调控抑制型受体表达的上游机制。本研究分别从组织/细胞系/分子/动物水平阐释USP9x/β-catenin相互作用在调控上述受体表达和TRAIL耐受中的关键作用，对逆转肺癌细胞的TRAIL耐受具有重要的理论意义。

Decoy receptor,including DcR1,DcR2,and OPG,is closely correlated with the TRAIL-resistance of tumor cells, but the regulated mechanism of decoy receptors expression is controversial.In our previous study,we found that β-catenin binding with TCF / LEF transcription factor regulated the transcription of decoy receptors,and deubiquitinase USP9x stabilized β-catenin in lung cancer cells.Consequently,we will take lung carcinoma as the target to research in this study, to analyze the correlation of the expression levels of USP9x/β-catenin and decoy receptors,including DcR1,DcR2,and OPG, to explore the transcription complex of β-catenin/TCF/LEF initiating the transcription of decoy receptors, and to explore USP9x deubiquitination of β-catenin. It is elucidated that the upstream mechanism of decoy receptors expression level regulated by β-catenin.Our study will explain USP9x and β-catenin interaction play a important role in TRAIL-resistance on the level of tissue / cells / molecules / animal,and may provide significantly theoretical basis for the combined treatment of lung carcinoma.