EPS8诱导的卵巢癌细胞阿米巴样迁移及其机制研究

卵巢癌转移以种植为主要途径，以细胞迁移为关键步骤。探讨卵巢癌细胞转移分子机制，对研发新型抗癌药、改善疾病预后有重要意义。我们前期的研究提示EPS8是引起卵巢癌细胞发生间充质样迁移信号通路中的关键因子，但其靶向抑制剂不能完全阻断卵巢癌细胞迁移。文献提示EPS8可以通过不同的结合方式，产生加帽与成束双重调节活性，控制肌动蛋白的动力学及结构组装。我们发现卵巢癌细胞可表现出阿米巴样迁移模式，EZRIN早期被招募到水泡膜上，随后EPS8出现。且EPS8-siRNA可抑制水泡的发生，并减少水泡细胞数目。由此推测：EZRIN通过EPS8调节肌动蛋白的成束和加帽活性促进胞体皮层张力和细胞内压力，形成“先导水泡”，使卵巢癌细胞发生阿米巴样迁移。本项目研究可望进一步明确卵巢癌转移的分子机制，为临床寻找针对卵巢癌转移的抗癌药物靶点及新药研发提供重要的理论依据。

Implantation metastasis is the main way of ovarian cancer metastasis, and cell migration is the key step. Exploring the molecular mechanism of ovarian cancer cell metastasis is of great significance for the development of new anticancer drugs and better prognosis of ovarian cancer patients. Our previous studies suggest that EPS8 is a key factor in the signal pathway that causes mesenchymal migration of ovarian cancer cells. However, targeted inhibitors of EPS8 cannot completely block the migration of ovarian cancer cells. Other studies suggest that EPS8 may have dual regulatory activities of bundling and capping through different binding mode and control the dynamics and structural assembly of actin. Our study found that ovarian cancer cells can exhibit an amoeboid migration pattern. EZRIN was recruited to the vesicular membrane in the early stage, and then EPS8 appeared. And EPS8-siRNA can inhibit the occurrence and reduce the number of blebs. So, we can assume that EZRIN may promote cortex tension and increase intracellular pressure through EPS8 to regulate bundling and capping activity of actin, forming " leader blebs" and causing ovarian cancer cells to undergo amoeboid migration. This project may further clarify the molecular mechanism of ovarian cancer metastasis and provide theoretical basis for the development of new anti-cancer drugs targeting ovarian cancer metastasis.