NRP1募集Miro1的重新定位维持结直肠癌细胞定向迁移的头导极性

微环境与肿瘤细胞相互作用，促进肿瘤细胞的定向迁移，维持细胞运动的方向性，提高肿瘤转移的有效性。我们前期研究，发现了结直肠癌细胞在血管内皮生长因子（VEGF）的刺激下，改变迁移方向，癌细胞头导端F-actin聚集，VEGF与其受体NRP1结合，募集Miro1聚集于癌细胞一端，可能维持癌细胞迁移的头导极性。本项目拟明确NRP1与Miro1的结合形式与结合位点，诱发癌细胞内线粒体重新定位的转运方式，阐述线粒体重新定位的能量效应和分子释放机制，解析NRP1、Miro1结合后诱发的信号转运途径，模拟中断NRP1、Miro1信号通路节点蛋白抗转移的有效性，分析节点蛋白表达与结直肠癌患者临床预后的相关性，确定NRP1、Miro1维持癌细胞的头导极性在肿瘤细胞定向迁移的关键作用。项目研究展现肿瘤转移机制的全新理念，为阻断肿瘤细胞迁移能力和干预肿瘤细胞迁移方向的抗转移治疗，提供分子信号靶点和理论依据。

Microenvironment interacting with cancer cells might promote directional migration, sustain motile directionality of cancer cells, and improve the efficiency of metastasis. In our previous study, we have found that the colorectal cancer cells changed their migration directionality when the direction of VEGF stimulation has been changed. F-actin concentrated on the leading edge of cancer cells as well. When VEGF linked its receptor, NRP1, Miro1 also aggregated at one end of the cancer cells. These findings indicated that the interaction between NRP1 and Miro1 might participate in maintaining the leading-edge polarity of cancer cells for migration. In this study, we attempt to find out the connecting patterns and the binding sites between NRP1 and Miro1, the transportation mode of intracellular mitochondria relocation, the energetic effects or release of possible molecules after mitochondrial relocation. Next, we try to explore the signal pathway provoked by NRP1 linked to Miro1, and the availability of simulating to interrupt keypoint proteins among NRP1/Miro1 pathway for anti-metastasis. After keypoint proteins expression has been linked to predict prognosis of patients with the colorectal cancer, we are sure that the leading-edge polarity of cancer cells may play a pivotal role on directional migration resulting from NRP1 and Miro1 connections. This study will bring about conceptual findings in the understanding of metastatic mechanism, and provide evidences of targeting methods for treatment of cancer metastasis based on blockage of migrating capacity and disturbance of migrating directionality toward cancer cells.