TIPE3调控整合素αvβ6质膜穿梭依赖的细胞运动促进结肠癌转移的机制研究

Our comprehensive research during the last 2 decades has confirmed that integrin αvβ6 is a critical factor promoting metastasis in colon cancer. However, the mechanism behind its function is rarely known around the world. On the basis of our latest novel findings on integrin αvβ6 trafficking and its specific promotor, TIPE3, we will further investigate the process of αvβ6 trafficking in order to reveal its mechanism in colon cancer cell migration. Our preliminary data indicated that TIPE3 regulated PIP2-dependent αvβ6 trafficking by capturing and transferring PIP2 with its unique hydrophobic cavity. Meanwhile, αvβ6 and TIPE3 are co-localized in colon cancer cells, which up-regulated and activated Rac1 respectively. We deduced that TIPE3 regulates αvβ6 trafficking by capturing and transferring PIP2, and TIPE3-αvβ6 shuttle complex is formed to promote the trafficking through Rac1-regulated actin reorganization, which could facilitate the migration of colon cancer cells by a positive feedback. We will explicate the mechanism of colon cancer cell migration from the cell structure dynamic level using critical techniques such as PLA and FRET. Our research will provide a potential treatment target for target therapy in colon cancer.

我们对整合素20余年研究证实αvβ6在结肠癌细胞迁移运动中发挥重要作用，但迄今国内外对其作用机制仍知之甚少。本课题是在我们最新发现的αvβ6质膜穿梭及其独特启动分子TIPE3的基础上，对αvβ6穿梭过程的深入研究，揭示αvβ6调控结肠癌细胞迁移运动的机制。前期实验提示：TIPE3具有特异性捕获并转运PIP2的空腔结构，能调控PIP2依赖的αvβ6质膜穿梭过程，同时结肠癌细胞内共定位的αvβ6与TIPE3可以分别上调与活化Rac1。我们推断，TIPE3通过转运PIP2调控αvβ6质膜穿梭运动，且TIPE3与αvβ6形成穿梭复合体，通过Rac1诱导的肌动蛋白聚集推动质膜穿梭过程，形成一正反馈，不断促进结肠癌细胞迁移。本研究拟通过多层次实验，利用临位连接、荧光共振能量转移等关键技术，从细胞的立体空间动态层面明确结肠癌细胞迁移运动的机制，为以αvβ6和TIPE3为靶点的结肠癌靶向治疗提供理论依据。

团队经过近20年深入研究证实整合素αvβ6在促进结肠癌恶性进展过程中发挥重要作用。前期研究证实，αvβ6在胞膜与胞质之间进行快速质膜穿梭运动，通过ERK-Ets1通路形成一正反馈机制促进结肠癌恶性进展。本研究通过多层次实验，利用内吞实验、胞吐实验、Capture-ELISA等关键技术，进一步深入探究了αvβ6质膜穿梭运动激活的下游通路在调控结肠癌恶性进展过程中的作用及相关分子机制，发现了整合素αvβ6可以作为多种上皮源性肿瘤的免疫组化标记物，对于预测淋巴结转移具有重要意义；整合素αvβ6可诱导结肠癌免疫微环境形成，促进微环境中成纤维细胞活化进而促进结肠癌恶性进展；探究了TIPE家族成员TIPE2和TIPE3在上皮源性肿瘤中的表达特点及作用，初步明确了其作用机制；此外，团队发现了flotillin-1可作为免疫组化标记物，在结肠癌恶性程度预测和预后评估过程中发挥重要作用。上述成果为以整合素αvβ6和TIPE家族成员为靶点对结肠癌进行预后分析及靶向治疗提供了重要的理论依据。