pEzrin-PIP2脂筏复合体调控CAPZA1“脱帽”促进肝癌细胞侵袭性伪足形成的机制

侵袭性伪足的形成在肝癌侵袭转移中发挥关键作用，而脂筏是调控伪足形成的重要平台，但具体机制未明。课题组前期发现：磷脂酰肌醇4，5-二磷酸（PIP2）作为脂筏的主要成分，可使结合在肌动蛋白丝（F-actin）正极的戴帽蛋白α1亚基（CAPZA1）“脱帽”；Ezrin作为PIP2和F-actin之间的关键连接分子，在肝癌中高表达，且与肝癌的侵袭转移潜能呈正相关。因此，我们推测：磷酸化的Ezrin（pEzrin）介导胞膜与骨架连接后，可在膜局部募集PIP2形成pEzrin-PIP2脂筏复合体，并通过其“手臂”作用将“戴帽”于F-actin正极上的CAPZA1拉向脂筏复合体，与PIP2发生作用并“脱帽”，肌动蛋白单体不断聚合在“无帽”状态的F-actin正极上，促进其延长并推动细胞膜向外凸起形成侵袭性伪足。拟在临床标本、细胞及动物模型上验证该假说，旨在为肝癌侵袭转移提供新的标志物和干预靶点。

The formation of invadopodia plays a key role in the invasion and metastasis of hepatocellular carcinoma (HCC), and lipid raft is an important platform to regulate the formation of invadopodia, but the specific mechanism is not clear. We found that in Pre-Experiments: Phosphoinositol 4, 5-diphosphate (PIP2), as the main component of lipid raft, can bind to CAPZA1 to "uncapping" and promote F-actin prolongation; Ezrin, as a key binding molecule between PIP2 and F-actin, is highly expressed in HCC and positively correlated with the invasion and metastasis of HCC. Therefore, we speculate that: Ezrin phosphorylation (pEzrin) mediating cell membrane and the cytoskeleton connection, which recruits PIP2 on membrane to form pEzrin-PIP2 lipid raft complex, and through its "arm" function, CAPZA1, which was "capped" on the F-actin barbed end, was pulled toward the lipid raft complex, on which interacting with PIP2 and will be released, and then actin monomers constantly polymerize on the "hatless" F-actin barbed end to promote its prolongation and promote the outward bulge of the cell membrane to form an invadopodia. This hypothesis is intended to be tested in clinical specimens, cells and animal models to provide new markers and intervention targets for HCC invasion and metastasis.