PIP2脂筏调控F-actin"踏车"促进肝癌细胞侵袭性伪足形成的机制研究

侵袭性伪足的形成在肝癌侵袭转移中发挥关键作用，F-actin细胞骨架重塑是侵袭性伪足形成的主要驱动力，而脂筏调控的F-actin有效延长是促进伪足形成的关键环节，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）脱落；HSP27以其磷酸化的形式穿梭于PIP2脂筏和F-actin负极之间，且在肝癌中高表达，与肝癌的侵袭转移潜能呈正相关。因此，我们推测：PIP2脂筏可从正负极两端同时调控F-actin的重塑，使其突破踏车现象，实现有效延长——其不仅可通过调控F-actin正极不断聚合延长以促进肝癌细胞膜凸起形成侵袭性伪足，而且还可通过抑制F-actin负极解聚以维持伪足内肌动蛋白细胞骨架的稳定。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). The remodeling of actin cytoskeleton is the main driving force for the formation of invadopodia, and the effective prolongation of F-actin regulated by lipid raft is the key steps to promote the invadopodia formation, but the specific mechanism remains unclear. 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; HSP27 could travel between PIP2 lipid raft and F-actin pointed end in its phosphorylation form, which is highly expressed in HCC, and positively correlated with the invasion and metastasis of HCC. Therefore, we speculate that: The PIP2 lipid raft regulates the remodeling of F-actin from both barded and pointed ends, facilitating F-actin to break the tread-milling and achieve effective prolongation -- PIP2 lipid raft not only promotes the formation of invadopodia by regulating the continuous polymerization of the barded end of F-actin, but also maintains the stability of the actin cytoskeleton inside the invadopodia by inhibiting the depolymerization of the pointed end of F-actin. This hypothesis is intended to be tested in clinical specimens, cells and animal models in order to provide new markers and intervention targets for blocking the invasion and metastasis of liver cancer.