HHEX在肺癌细胞中高表达，并与转移相关，但其调控肺癌细胞转移的机制并不清楚。前期实验表明，HHEX调控转移相关蛋白和EMT；敲低HHEX表达降低肺癌细胞迁移能力和F-actin聚合，且ROCK1、RhoA-GTP和p-Cofilin水平下降；IP实验表明HHEX与Rho-GDI （ARHGDIA）存在相互作用。基于此，提出假说：在肺癌细胞中，HHEX调控TWIST1和SNAI2的表达促进EMT发生；HHEX也能通过CD81在质膜上与ARHGDIA结合，发挥类似GDF的作用，释放并活化Rho家族蛋白，通过ROCK1/PAK1-LIMK-Cofilin或ROCK1-MLC通路调控F-actin的聚合和重构，影响肺癌细胞的迁移和侵袭能力。我们的目的是利用细胞和动物模型及组织芯片，探讨HHEX在肺癌细胞中调控EMT及肺癌细胞转移的机制，为深入了解肿瘤转移调控网络和寻找抗转移新靶标提供依据。

HHEX is overexpressed in lung cancer cells and associated with cancer metastasis. However, the molecular mechanism underlying its roles remains unclear. According to our preliminary data, we found HHEX modulated metastasis-related proteins and EMT. HHEX knockdown using RNAi technique decreased the levels of ROCK1, Rho A-GTP and p-Cofilin as well as the F-actin polymerization and cell migration. Moreover, HHEX interacted with Rho-GDI (ARHGDIA) physically. Thus, we raise a hypothesis: HHEX regulates EMT by up-regulation of TWIST1 and SNAI2 at the transcriptional level. HHEX binds to ARHGDIA through CD81 on the plasma membrane as a GDF, releasing and activating the Rho family of small GTPases. The activated Rho-GTP promotes F-actin remodeling and polymerization via the signaling axes including ROCK1/PAK1-LIMK-p-Cofilin or ROCK1-MLC, leading to enhancement of cell migration and invasion eventually. Accordingly, the present project is going to use cell and animal models and tissue array to elucidate the molecular mechanism underlying the role of HHEX in EMT process as well as the functions of HHEX in enhancing F-actin remodeling and migration in lung cancer cells. Hopefully, the study of HHEX can help us understand the metastatic signaling network in lung cancer cells. In addition, it will be helpful for developing the novel anti-metastasis targets for cancer therapy in the future.