Tan Jie, Li Xueshi, Wang Yuguang, Wang Lin, Zhao Xingguo, Wang Yixu, Cui Meng
Department of Otorhinolaryngology Head and Neck Surgery, Peking University People's Hospital, Peking University, Beijing, PR China.
Department of Head and Neck Thyroid, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, PR China.
Cell Death Discov. 2025 Jul 21;11(1):333. doi: 10.1038/s41420-025-02634-2.
To elucidate the role of eukaryotic translation initiation factor 3 subunit B (EIF3B) in laryngeal squamous cell carcinoma (LSCC) progression and its regulatory mechanism. Integrated bioinformatics analysis (GEO, TCGA), immunohistochemistry (IHC), lentiviral-mediated gene knockdown/overexpression, co-immunoprecipitation (Co-IP), Western blotting (WB), and in vivo xenograft models were employed. Clinically, our findings revealed an upregulation of EIF3B expression in LSCC, with its abnormally high levels significantly correlating with poor survival outcomes among patients. Functionally, ablation of EIF3B potently inhibited cancer cell proliferation, colony formation, and migratory abilities. Mechanistically, EIF3B stabilized MAP2K2 via direct interaction with its P3 domain, inhibiting VHL-mediated ubiquitination at K169. Notably, MAP2K2 kinase activity was essential for EIF3B-driven ERK phosphorylation and downstream oncogenic signaling. Moreover, EIF3B overexpression accelerated tumor growth in xenograft models, which was rescued by MAP2K2 knockdown. In Conclusion, EIF3B promotes LSCC progression by stabilizing MAP2K2, activating the ERK/MAPK pathway, and disrupting VHL-mediated proteostasis. Targeting the EIF3B-MAP2K2 axis may offer therapeutic strategies for LSCC.
为阐明真核生物翻译起始因子3亚基B（EIF3B）在喉鳞状细胞癌（LSCC）进展中的作用及其调控机制。采用了综合生物信息学分析（GEO、TCGA）、免疫组织化学（IHC）、慢病毒介导的基因敲低/过表达、免疫共沉淀（Co-IP）、蛋白质免疫印迹（WB）和体内异种移植模型。临床上，我们的研究结果显示LSCC中EIF3B表达上调，其异常高水平与患者的不良生存结果显著相关。功能上，EIF3B的缺失有力地抑制了癌细胞的增殖、集落形成和迁移能力。机制上，EIF3B通过与其P3结构域直接相互作用稳定MAP2K2，抑制VHL介导的K169位点泛素化。值得注意的是，MAP2K2激酶活性对于EIF3B驱动的ERK磷酸化和下游致癌信号传导至关重要。此外，EIF3B过表达加速了异种移植模型中的肿瘤生长，而MAP2K2敲低可挽救这一现象。总之，EIF3B通过稳定MAP2K2、激活ERK/MAPK途径和破坏VHL介导的蛋白质稳态促进LSCC进展。靶向EIF3B-MAP2K2轴可能为LSCC提供治疗策略。
