F-actin dynamics is crucial for many fundamental properties of cancer cells, from cell-substrate adhesion to migration, invasion and metastasis. However, the regulatory mechanisms of actin dynamics are still incompletely understood. In this study, we demonstrate the function of a protein named TM9SF4 in regulating actin dynamics and controlling cancer cell motility and metastasis. We show that an N-terminal fragment (NTF) cleaved from TM9SF4 can directly bind to F-actin to induce actin oxidation at Cys374, consequently enhancing cofilin-mediated F-actin disassembly. Knockdown of TM9SF4 reduces cell migration and invasion in ovarian cancer cells A2780, SKOV3 and several high grade serous ovarian cancer lines (HGSOCs). In vivo, knockdown of TM9SF4 completely abolishes the tumor growth and metastasis in athymic nude mice. These data provide mechanistic insights into TM9SF4-mediated regulation of actin dynamics in ovarian cancer cells.

F-肌动蛋白动力学对于癌细胞的许多基本特性至关重要，从细胞-基质粘附到迁移、侵袭和转移。然而，肌动蛋白动力学的调节机制仍未完全了解。在这项研究中，我们展示了一种名为 TM9SF4 的蛋白质在调节肌动蛋白动力学和控制癌细胞运动和转移方面的功能。我们表明，从 TM9SF4 切割的 N 末端片段 (NTF) 可以直接与 F-肌动蛋白结合，在 Cys374 处诱导肌动蛋白氧化，从而增强 cofilin 介导的 F-肌动蛋白分解。TM9SF4 的敲低减少了卵巢癌细胞 A2780、SKOV3 和几种高级浆液性卵巢癌细胞系 (HGSOC) 中的细胞迁移和侵袭。在体内，TM9SF4 的敲低完全消除了无胸腺裸鼠的肿瘤生长和转移。