淋巴结转移是膀胱癌患者预后不良的主要原因，目前亟待阐明膀胱癌淋巴结转移的分子机制,以发现新的治疗靶点。Arp2/3蛋白复合体在肿瘤细胞肌动蛋白聚集成丝、伪足形成、运动迁移方面发挥着重要的作用。课题组前期发现Arp2/3复合体各亚基在膀胱癌组织中高表达，敲低各亚基后发现ARPC4亚基能够最为显著地抑制膀胱癌细胞的迁移，免疫共沉淀实验发现ARPC4能够与WASF2蛋白相结合，而PI3K/AKT-Rac1信号通路在激活WASF2蛋白、促进细胞迁移中发挥重要作用；结合前期预实验的结果，我们进一步提出PI3K/AKT-ELK1调控ARPC4表达的新机制。本研究拟通过体内外实验，确定Arp2/3复合体亚基ARPC4由PI3K/ATK通过Rac1和ELK1双通路的调控，并阐明它在膀胱癌淋巴结转移中的分子机制，为靶向膀胱癌淋巴结转移新的治疗策略及新靶点的发现提供科学依据。

Lymph node metastasis is the main reason for the poor outcome of bladder cancer patients. It is urgent to clarify the molecular mechanisms underlying lymph node metastasis and explore novel therapeutic targets for bladder cancer treatment. The Arp2/3 complex plays important roles in actin polymerization, invadopodia formation and migration of tumor cells. Our team found that the expression of Arp2/3 complex subunits was significant higher in bladder cancer tissues as compared with adjacent normal tissues. Knockdown of the ARPC4 subunit exerted the most significant inhibition to the migration of tumor cells among all of the subunits. We affirmed that ARPC4 binded to WASF2 using Co-immunoprecipitation (Co-IP) technique, in which the PI3K/AKT-Rac1 signaling pathway was vital to the activation of WASF2 to promote cellular migration. In this proposal, we provided a novel mechanism that the PI3K/AKT signaling pathway modulated the ARPC4 subunit in lymph node metastasis of bladder cancer via dual pathways by simultaneously activating PI3K/ATK-Rac1 and PI3K/ATK-EKL1 signaling pathways. Our work will provide a scientific clue for the discovery of novel therapeutic targets for targeting lymph node metastasis in the treatment of bladder cancer.