IGF2BP3 enhances ferroptosis resistance in colon cancer by stabilizing SLC7A11 mRNA and is regulated by miR-98-5p
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, with increasing incidence and mortality rates. Resistance to cell death is a hallmark of cancer, and ferroptosis, a form of non-apoptotic cell death, has emerged as a critical factor in tumor suppression. The RNA-binding protein IGF2BP3, which plays a significant role in colon cancer progression, has been shown to modulate various oncogenic processes. However, its involvement in ferroptosis regulation in colon cancer remains largely unexplored. This study investigates the role of IGF2BP3 in ferroptosis regulation and its potential as a therapeutic target in colon cancer. Our data show that IGF2BP3 is upregulated in colon cancer tissues and correlates with poor prognosis. Knockdown of IGF2BP3 in colon cancer cell lines enhances sensitivity to ferroptosis induction, evidenced by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, which are reversed by the ferroptosis inhibitor ferrostatin-1. Mechanistically, IGF2BP3 regulates ferroptosis by stabilizing SLC7A11 mRNA, a key ferroptosis regulator, through its interaction with the mRNA. Additionally, miR-98-5p directly targets IGF2BP3, enhancing ferroptosis sensitivity. In vivo studies confirm that IGF2BP3 knockdown suppresses tumor growth, highlighting its potential as a therapeutic target. Overall, our findings suggest that IGF2BP3 plays a pivotal role in regulating ferroptosis in colon cancer, offering new avenues for therapeutic strategies in colon cancer treatment. Overall design: RNA-seq profiling of three pairs of negative control and IGF2BP3 KD HCT116 cells.