AUTHOR=Zhang Qi , Liu Xiaoyu , Chen Yukan , Wang Ruilin , Zhao Shuangyan , Tian Yuting , Li Shuping , Liu Xiaojun 

TITLE=IGF2BP2 regulates gastric cancer radiotherapy resistance through HIF1α-mediated glycolysis

JOURNAL=Frontiers in Oncology

VOLUME=Volume 15 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1512177

DOI=10.3389/fonc.2025.1512177

ISSN=2234-943X

ABSTRACT=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 m6A-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 m6A-modified “GGACU” motif within the coding region of HIF1α mRNA, positively regulating HIF1α mRNA stability and protein expression in an m6A-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.