研究证实ATX/LPAR信号轴及Hippo 信号通路在胰腺癌发生发展中起重要作用。课题组前期研究发现FoxM1在胰腺癌高表达，上调FoxM1可促进ATX、LPAR的表达及LPA的产生。而LPA是Hippo信号通路最重要的上游调控因子之一，Hippo效应分子YAP又可促进FoxM1表达。由此提出假说：FoxM1通过转录调节ATX/LPAR信号轴，促进LPA产生，进而抑制Hippo信号通路，促进YAP入核和转录活性，上调FoxM1表达，形成FoxM1-ATX/LPAR-Hippo正反馈环路。本研究拟构建ATX和LPAR启动子区各种缺失突变体，采用Chip、EMSA等探讨FoxM1是否直接结合ATX和LPAR启动子区发挥转录调控作用，以LPA处理胰腺癌细胞系后观察Hippo信号通路的活化状态以及FoxM1表达水平的变化，阐明该正反馈环路促进胰腺癌的作用机理，以期为胰腺癌的预防及诊治提供新思路。

The ATX/LPAR signaling axis and the Hippo signaling pathway play tivotal roles during the occurrence and development of this cancer. Previous study showed that pancreatic cancer had high expression of FoxM1,whereas upregulation of FoxM1 expression may promote expression of ATX and LPAR, and facilitate generation of LPA. LPA was proved as one of the most important regulator of Hippo signaling pathway, and YAP, the effector of the Hippo pathway could increase FoxM1 expression. Thereout, we proposed hypothesis: FoxM1 increased the generation of LPA through transcriptional regulation of ATX/LPAR axis, and promoted YAP nuclear translocation and improved the transcription activity, which could upregulation of FoxM1 expression, which formed finally a FoxM1-ATX/LPAR-Hippo positive feedback loop. Our study will investigate the role of FoxM1 on the generation of LPA and the expression of ATX and LPAR in pancreatic cancer cell lines. By construction of deletion mutant in ATX and LPAR promoter region， we will verify the contribution of FoxM1 on these two promoters transcription. Further, the ChIP and EMSA will be adopted to investigate whether the regulation role of FoxM1 is based on the direct binding with ATX and LPAR promoters. Finally, we will inspect the activity of Hippo signaling pathway and the expression level of FoxM1 after treating with LPA.