磷酸酶PP4R1调控JNK信号通路参与肺癌相关成纤维细胞介导肺癌早期结节发生的分子机制

CAFs plays a crucial role in the raising, activation, proliferation and formation of vascular buds of tumor vascular endothelial cells.The early stage of the study let us pay attention to the expression of phosphatase PP4R1 rose significantly in expression of lung cancer cells stimulated by CAFs (10.73 times),maybe it has potential function in the process of malignant proliferation of lung cancer cells mediated by CAFs.At the same time,we also confirmed that the JNK signaling pathway plays an important role in the process of malignant proliferation of lung cancer regulate by PP4R1.In the following study, we will conduct in-depth research on the molecular mechanisms that CAFs promoted the formation of malignant phenotype of lung cancer cells.On the one hand,we will analyse cytokines spectrum that CAFS secreted in vitro,to identify the key factor of the ability of proliferation and migration of lung cancer cells.On the other hand,we will analyse why the expression of PP4R1 rose and JNK signaling pathway activated,and verify regulating effect of JNK signaling pathway by PP4R1.In addition,we will focus on researching expression of PP4R1 in a large-scale clinical tissue samples of lung cancer,especially in the early ground-glass opacity of lung cancer,to analyse the relationship between PP4R1 and staging and prognosis of lung cancer,and to provide the molecular basis to analyze the occurrence of early ground-glass opacity of lung cancer.

CAFs在肿瘤血管内皮细胞的募集、活化、增殖和血管芽的形成中扮演着关键角色。前期研究让我们关注到一个磷酸酶PP4R1的表达在CAFs刺激的肺癌细胞中表达显著上调（10.73倍），可能在CAFs介导的肺癌细胞恶性增殖的过程中具有潜在功能。同时我们也证实了JNK信号通路在PP4R1对肺癌的恶性增殖调节过程中发挥重要角色。在接下来的研究中，我们将就CAFs促进肺癌细胞恶性表型形成的分子机制进行深入研究。一方面，体外分析CAFs分泌的细胞因子谱，鉴定对肺癌细胞增殖迁移侵袭能力的关键因子。另一方面，分析PP4R1的表达上调和JNK信号通路激活的原因，以及验证PP4R1对JNK信号通路的调控作用。此外，重点研究PP4R1在大规模肺癌临床组织标本尤其是肺癌早期毛玻璃结节中的表达情况，分析PP4R1与肺癌分期、预后的关系，为解析肺癌的早期毛玻璃结节的发生提供分子基础。

CAFs在肿瘤血管内皮细胞的募集、活化、增殖和血管芽的形成中扮演着关键角色。前期研究让我们关注到一个磷酸酶PP4R1的表达在CAFs刺激的肺癌细胞中表达显著上调（10.73倍），可能在CAFs介导的肺癌细胞恶性增殖的过程中具有潜在功能。在本项目的研究中，我们在临床样本检测和数据库数据分析中均证实PP4R1在肺癌中高表达，高表达PP4R1的肺癌患者预后较差。敲低PP4R1后，细胞的迁移、增殖能力减弱，上皮相关标志蛋白表达水平增加，间叶相关标志蛋白表达水平减少，质谱实验发现PP4R1的结合蛋白HMGA2，证实HMGA2参与了PP4R1的功能发挥，并且对JNK信号通路有调控作用。本研究初步揭示PP4R1发挥功能的分子机制，为肺癌的治疗提供一个潜在的靶点。