Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Changsha 410078, PR China.
Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, PR China.
Biochem Pharmacol. 2023 Jul;213:115616. doi: 10.1016/j.bcp.2023.115616. Epub 2023 May 19.
Cancer stem cells (CSCs) are the leading cause of recurrence and poor prognosis in non-small cell lung cancer (NSCLC). Eukaryotic translation initiation factor 3a (eIF3a) participates in many tumor development processes, such as metastasis, therapy resistance, and glycolysis, all of which are closely associated with the presence of CSCs. However, whether eIF3a maintains NSCLC-CSC-like properties remains to be elucidated. In this study, eIF3a was highly expressed in lung cancer tissues and was linked to poor prognosis. eIF3a was also highly expressed in CSC-enriched spheres compared with adherent monolayer cells. Moreover, eIF3a is required for NSCLC stem cell-like traits maintenance in vitro and in vivo. Mechanistically, eIF3a activates the Wnt/β-catenin signaling pathway, promoting the transcription of cancer stem cell markers. Specifically, eIF3a promotes the transcriptional activation of β-catenin and mediates its nuclear accumulation to form a complex with T cell factor 4 (TCF4). However, eIF3a has no significant effect on protein stability and translation. Proteomics analysis revealed that the candidate transcription factor, Yin Yang 1 (YY1), mediates the activated effect of eIF3a on β-catenin. Overall, the findings of this study implied that eIF3a contributes to the maintenance of NSCLC stem cell-like characteristics through the Wnt/β-catenin pathway. eIF3a is a potential target for the treatment and prognosis of NSCLC.
癌症干细胞（CSCs）是非小细胞肺癌（NSCLC）复发和预后不良的主要原因。真核翻译起始因子 3a（eIF3a）参与许多肿瘤的发展过程，如转移、治疗耐药和糖酵解，所有这些过程都与 CSCs 的存在密切相关。然而，eIF3a 是否维持 NSCLC-CSC 样特性仍有待阐明。在这项研究中，eIF3a 在肺癌组织中高表达，并与不良预后相关。eIF3a 在富含 CSC 的球体中也比贴壁单层细胞中高表达。此外，eIF3a 在体外和体内维持 NSCLC 干细胞样特性是必需的。在机制上，eIF3a 激活了 Wnt/β-catenin 信号通路，促进了癌症干细胞标志物的转录。具体来说，eIF3a 促进了 β-catenin 的转录激活，并介导其核积累，与 T 细胞因子 4（TCF4）形成复合物。然而，eIF3a 对蛋白质稳定性和翻译没有显著影响。蛋白质组学分析表明，候选转录因子 Yin Yang 1（YY1）介导了 eIF3a 对 β-catenin 的激活作用。总的来说，这项研究的结果表明，eIF3a 通过 Wnt/β-catenin 通路促进了 NSCLC 干细胞样特征的维持。eIF3a 是治疗和预测 NSCLC 的潜在靶点。
