Targeting IGF2BP2-CEMIP Boosts Antiangiogenic Therapy in Colorectal Cancer in Mice

Weikang Chen; Haojie Bai; Yani Huo; Yifan Wu; Wei Kang; Dong Zhang; Yongxin Zhang; Shiyan Wang; Lixia Xu; Chi Chun Wong; Ka Fai To; Xiaoxing Li; Jun Yu

doi:10.1016/j.eng.2025.06.035

Engineering ›› 2025, Vol. 52 ›› Issue (9) :229 -243. DOI: 10.1016/j.eng.2025.06.035

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Targeting IGF2BP2-CEMIP Boosts Antiangiogenic Therapy in Colorectal Cancer in Mice

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Abstract

Angiogenesis is essential for supporting tumor progression and metastasis. However, the potential role of the epitranscriptome in regulating angiogenesis remains unclear. Here, we identify the RNA N⁶-methyladenosine (m⁶A) reader insulin-like growth factor 2 (IGF2) messenger RNA (mRNA)-binding protein 2 (IGF2BP2) as the top enriched m⁶A regulator in hypervascular colorectal cancer (CRC), with its expression correlating with poor prognosis. Knockdown of IGF2BP2 in CRC cells suppressed their ability to promote pro-angiogenic phenotypes in endothelial cells in vitro, as well as vascular abnormalization, tumor progression, and metastasis in vivo. Supporting these findings, intestine-specific Igf2bp2 knock-in mice exhibited accelerated azoxymethane (AOM) plus dextran sulfate sodium (DSS)-induced CRC through enhanced angiogenesis and vascular abnormalities, whereas intestine-specific Igf2bp2 knockout inhibited tumor growth by normalizing tumor vasculature. Mechanistically, IGF2BP2 binds to m⁶A-modified cell migration inducing and hyaluronan binding protein (CEMIP) mRNA and enhanced its stability, leading to increased secretion of CEMIP. Secreted CEMIP interacts with membrane glucose-regulated protein 78 (GRP78) on endothelial cells, activating pro-angiogenic signaling. Importantly, targeting IGF2BP2 through genetic ablation, lipid nanoparticle (LNP)-encapsulated small interfering IGF2BP2, or the chemical inhibitor (CWI1-2) synergized with anti-angiogenic drugs to suppress tumor growth in multiple CRC models. Together, these findings suggest that targeting IGF2BP2 is a promising strategy to enhance the efficacy of anti-angiogenic therapy in CRC.

Keywords

Colorectal cancer / N⁶-methyladenosine modification / Insulin-like growth factor 2 mRNA-binding protein 2 / Angiogenesis / Cell migration inducing and hyaluronan binding protein

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Weikang Chen, Haojie Bai, Yani Huo, Yifan Wu, Wei Kang, Dong Zhang, Yongxin Zhang, Shiyan Wang, Lixia Xu, Chi Chun Wong, Ka Fai To, Xiaoxing Li, Jun Yu. Targeting IGF2BP2-CEMIP Boosts Antiangiogenic Therapy in Colorectal Cancer in Mice. Engineering, 2025, 52(9): 229-243 DOI:10.1016/j.eng.2025.06.035

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