Epithelial ovarian cancer is the most lethal gynecological malignant tumor. Although debulking surgery, chemotherapy, and PARP inhibitors have greatly improved survival, the prognosis for patients with advanced EOC without HRD is still poor.LLGL2, as a cell polarity factor, is involved in maintaining cell polarity and asymmetric cell division. In the study of zebrafish development,LLGL2regulated the proliferation and migration of epidermal cells and the formation of cortical F-actin. However, the role ofLLGL2in ovarian cancer has not been described. Our study found, through bioinformatics analysis, that low expression ofLLGL2was significantly associated with a more advanced stage and a higher grade of EOC and a poorer survival of patients. Functional experiments that involvedLLGL2overexpression and knockdown showed thatLLGL2inhibited the migration and invasion abilities of ovarian cancer cells in vitro, without affecting their proliferation. LLGL2-overexpressing mice had fewer metastatic implant foci than the controls in vivo. Mechanistically, immunoprecipitation combined with mass spectrometry analysis suggested that LLGL2 regulated cytoskeletal remodeling by interacting with ACTN1. LLGL2 altered the intracellular localization and function of ACTN1 without changing its protein and mRNA levels. Collectively, we uncovered that LLGL2 impaired actin filament aggregation into bundles by interacting with ACTN1, which led to cytoskeleton remodeling and inhibition of the invasion and metastasis of ovarian cancer cells.
上皮性卵巢癌是最致命的妇科恶性肿瘤。尽管减瘤手术、化疗及PARP抑制剂的应用显著改善了患者生存，但对于缺乏同源重组缺陷的晚期上皮性卵巢癌患者，其预后仍然较差。LLGL2作为细胞极性因子，参与维持细胞极性与不对称细胞分裂。在斑马鱼发育研究中，LLGL2调控表皮细胞增殖迁移及皮层F-肌动蛋白形成。然而，LLGL2在卵巢癌中的作用尚未被阐明。本研究通过生物信息学分析发现，LLGL2低表达与上皮性卵巢癌更高分期、更高级别及更差患者生存显著相关。通过LLGL2过表达与敲低的功能实验表明，LLGL2在体外抑制卵巢癌细胞的迁移侵袭能力，但不影响其增殖。在体内实验中，LLGL2过表达小鼠的转移灶数量较对照组显著减少。机制上，免疫沉淀联合质谱分析提示LLGL2通过与ACTN1相互作用调控细胞骨架重塑。LLGL2改变了ACTN1的细胞内定位与功能，而不影响其蛋白及mRNA水平。综上，本研究发现LLGL2通过与ACTN1相互作用，破坏肌动蛋白丝聚集成束，从而引起细胞骨架重塑，最终抑制卵巢癌细胞的侵袭与转移。
LLGL2Inhibits Ovarian Cancer Metastasis by Regulating Cytoskeleton Remodeling viaACTN1
肿瘤(癌症)患者之家