Zhang Qi, Liu Xiaoyu, Chen Yukan, Wang Ruilin, Zhao Shuangyan, Tian Yuting, Li Shuping, Liu Xiaojun
The First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou, Gansu, China.
Xi'an International Medical Center Hospital, Xian, Shanxi, China.
Front Oncol. 2025 May 16;15:1512177. doi: 10.3389/fonc.2025.1512177. eCollection 2025.
This study reveals the core mechanism by which insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) drives tumor progression and radiotherapy resistance in gastric cancer (GC) through mA-dependent regulation of hypoxia-inducible factor 1α (HIF1α). Clinical analyses show that IGF2BP2 is significantly overexpressed in gastric cancer tissues, and its expression level is closely associated with tumor size and poor patient prognosis. Functional studies demonstrate that elevated expression of IGF2BP2 accelerates the transition of gastric cancer cells from the G1 phase to the G2/M phase of the cell cycle and markedly enhances cell proliferation and migration through anti-apoptotic effects. Mechanistically, IGF2BP2 specifically binds to the mA-modified "GGACU" motif within the coding region of HIF1α mRNA, positively regulating HIF1α mRNA stability and protein expression in an mA-dependent manner. High IGF2BP2 expression significantly enhances glycolytic activity in gastric cancer cells, while overexpression of HIF1α partially rescues the suppression of malignant phenotypes caused by IGF2BP2 knockdown, indicating that HIF1α serves as a key downstream effector mediating the oncogenic role of IGF2BP2 in gastric cancer. Furthermore, knockdown of IGF2BP2 significantly increases radiosensitivity by exacerbating DNA damage and enhancing oxidative stress.
本研究揭示了胰岛素样生长因子2信使核糖核酸结合蛋白2（IGF2BP2）通过对缺氧诱导因子1α（HIF1α）的N6-甲基腺嘌呤（m⁶A）依赖性调控来驱动胃癌（GC）肿瘤进展和放疗抵抗的核心机制。临床分析表明，IGF2BP2在胃癌组织中显著过表达，其表达水平与肿瘤大小及患者预后不良密切相关。功能研究表明，IGF2BP2表达升高加速胃癌细胞从细胞周期的G1期向G2/M期转变，并通过抗凋亡作用显著增强细胞增殖和迁移。机制上，IGF2BP2特异性结合HIF1α信使核糖核酸编码区内m⁶A修饰的“GGACU”基序，以m⁶A依赖性方式正向调节HIF1α信使核糖核酸稳定性和蛋白表达。高IGF2BP2表达显著增强胃癌细胞的糖酵解活性，而HIF1α过表达部分挽救了因IGF2BP2敲低导致的恶性表型抑制，表明HIF1α作为关键的下游效应因子介导IGF2BP2在胃癌中的致癌作用。此外，敲低IGF2BP2通过加剧DNA损伤和增强氧化应激显著增加放射敏感性。
