He Na, Wei Xinyuan, Sun Ruofei, Zhang Gengyuan, Zhao Jie, Jiang Xiangyan, Long Bo, Yu Zeyuan, Shi Wengui, Jiao Zuoyi
Department of Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu, China; The Second Clinical Medical College, Lanzhou University, Gansu, China.
Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
Gene. 2025 Jul 5;955:149458. doi: 10.1016/j.gene.2025.149458. Epub 2025 Apr 3.
Eg5, also known as KIF11, is a motor protein essential for establishing a bipolar spindle and ensuring proper chromosome congression during mitosis. It is amplified in various human cancers and serves as a critical oncogene driving tumour progression. However, the role and clinical significance of Eg5 in gastric cancer has remained elusive. In this study, we showed that Eg5 is upregulation in gastric cancer tissues and is negatively associated with patient prognosis. The ablation of Eg5 inhibits the proliferation and migration of gastric cancer cells and suppresses tumour growth in xenograft mice. Mechanistically, Eg5 ablation induces the formation of monopolar spindle, leading to cell apoptosis and consequent inhibition of tumour growth. Furthermore, Arry520 is demonstrated as a potent Eg5 inhibitor which blocks tumour growth by increasing the formation of cell monopolar spindle and inducing apoptosis. Arry520 exhibits efficiently therapeutic effects on gastric cancer in tumour organoid models, cell-derived xenografts and patient-derived xenografts (PDX) in mice. Collectively, our findings provide evidence for the oncogenic properties of the mitotic protein Eg5 and identify Arry520 as a promising strategy to combat gastric cancer.
Eg5，也被称为KIF11，是一种驱动蛋白，对于在有丝分裂期间建立双极纺锤体并确保染色体正确排列至关重要。它在多种人类癌症中发生扩增，并作为驱动肿瘤进展的关键癌基因。然而，Eg5在胃癌中的作用和临床意义仍不明确。在本研究中，我们发现Eg5在胃癌组织中上调，且与患者预后呈负相关。敲除Eg5可抑制胃癌细胞的增殖和迁移，并抑制异种移植小鼠中的肿瘤生长。从机制上讲，敲除Eg5会诱导单极纺锤体的形成，导致细胞凋亡并进而抑制肿瘤生长。此外，Arry520被证明是一种有效的Eg5抑制剂，它通过增加细胞单极纺锤体的形成并诱导凋亡来阻断肿瘤生长。Arry520在小鼠肿瘤类器官模型、细胞来源的异种移植模型和患者来源的异种移植模型（PDX）中对胃癌均表现出有效的治疗效果。总体而言，我们的研究结果为有丝分裂蛋白Eg5的致癌特性提供了证据，并确定Arry520是对抗胃癌的一种有前景的策略。
