Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China.
Department of Gynecology, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China.
J Mol Med (Berl). 2024 Nov;102(11):1395-1410. doi: 10.1007/s00109-024-02486-w. Epub 2024 Sep 24.
Eukaryotic initiation factor 4A-3 (EIF4A3) is a key component of the exon junction complex (EJC) and is extensively involved in RNA splicing, inducing mRNA decay, and regulating the cell cycle and apoptosis. However, the potential role of EIF4A3 in EC has not been comprehensively investigated and remains unknown. Here, we report that the expression level of EIF4A3 is dramatically elevated in endometrial cancer (EC) samples compared with normal EC samples via bioinformatics analysis and immunohistochemistry analysis, and that high expression of EIF4A3 promotes the proliferation, migration, and invasion of EC cells. Mechanistically, we found that high EIF4A3 expression stabilized cell division cyclin 20 (CDC20) mRNA, and high EIF4A3 expression induced pro-carcinogenic effects in EC cells that were efficiently antagonized upon knockdown of CDC20, as well as Apcin, an inhibitor of CDC20. These findings reveal a novel mechanism by which high expression of EIF4A3 induces CDC20 upregulation, thus leading to EC tumorigenesis and metastasis, indicating a potential treatment strategy for EC patients with high EIF4A3 expression using Apcin. KEY MESSAGES: The expression level of EIF4A3 was dramatically elevated in endometrial cancer (EC) samples compared with normal endometrial cancer samples. High EIF4A3 expression stabilized CDC20 mRNA, and high EIF4A3 expression induced pro-carcinogenic effect in EC cells which was efficiently antagonized upon knockdown of CDC20. Apcin, an inhibitor of CDC20, could effectively counteract high expression of EIF4A3 inducing EC tumourigenesis and metastasis, indicating the potential treatment strategy for EC patients with EIF4A3 high expression by using Apcin.
真核翻译起始因子 4A-3（EIF4A3）是外显子结合复合体（EJC）的关键组成部分，广泛参与 RNA 剪接、诱导 mRNA 降解以及调控细胞周期和细胞凋亡。然而，EIF4A3 在 EC 中的潜在作用尚未得到全面研究，目前仍不清楚。在这里，我们通过生物信息学分析和免疫组织化学分析报道，EIF4A3 在子宫内膜癌（EC）样本中的表达水平明显高于正常 EC 样本，并且高表达的 EIF4A3 促进了 EC 细胞的增殖、迁移和侵袭。从机制上讲，我们发现高表达的 EIF4A3 稳定了细胞分裂周期蛋白 20（CDC20）mRNA，并且高表达的 EIF4A3 在 EC 细胞中诱导了致癌前效应，而在敲低 CDC20 或使用 CDC20 抑制剂 Apcin 后，这些效应得到了有效拮抗。这些发现揭示了一种新的机制，即高表达的 EIF4A3 诱导 CDC20 上调，从而导致 EC 肿瘤发生和转移，这表明使用 Apcin 可能成为治疗 EIF4A3 高表达的 EC 患者的潜在策略。
EIF4A3 在子宫内膜癌（EC）样本中的表达水平明显高于正常子宫内膜癌样本。高 EIF4A3 表达稳定了 CDC20 mRNA，高 EIF4A3 表达在 EC 细胞中诱导致癌前效应，而敲低 CDC20 可有效拮抗这一效应。CDC20 的抑制剂 Apcin 可有效拮抗 EIF4A3 高表达诱导的 EC 肿瘤发生和转移，这表明使用 Apcin 可能成为治疗 EIF4A3 高表达的 EC 患者的潜在策略。
