Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Cell Death Dis. 2023 Sep 1;14(9):581. doi: 10.1038/s41419-023-06099-y.
Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an RNA-binding protein, is associated with tumorigenesis and progression. However, the exact molecular mechanisms of IGF2BP3 in colorectal cancer (CRC) oncogenesis, progression, and drug resistance remain unclear. This study found that IGF2BP3 was upregulated in CRC tissues. Clinically, the elevated IGF2BP3 level is predictive of a poor prognosis. Functionally, IGF2BP3 enhances CRC tumorigenesis and progression both in vitro and in vivo. Mechanistically, IGF2BP3 promotes epidermal growth factor receptor (EGFR) mRNA stability and translation and further activates the EGFR pathway by serving as a reader in an N6-methyladenosine (mA)-dependent manner by cooperating with METTL14. Furthermore, IGF2BP3 increases the drug resistance of CRC cells to the EGFR-targeted antibody cetuximab. Taken together, our results demonstrated that IGF2BP3 was a functional and clinical oncogene of CRC. Targeting IGF2BP3 and mA modification may therefore offer rational therapeutic targets for patients with CRC.
胰岛素样生长因子 2 mRNA 结合蛋白 3（IGF2BP3）是一种 RNA 结合蛋白，与肿瘤的发生和发展有关。然而，IGF2BP3 在结直肠癌（CRC）发生、进展和耐药性中的确切分子机制仍不清楚。本研究发现 IGF2BP3 在 CRC 组织中上调。临床上，IGF2BP3 水平升高预示预后不良。功能上，IGF2BP3 增强 CRC 的体外和体内肿瘤发生和进展。在机制上，IGF2BP3 通过与 METTL14 合作，以 N6-甲基腺苷（m6A）依赖性方式作为阅读器，促进表皮生长因子受体（EGFR）mRNA 的稳定性和翻译，从而进一步激活 EGFR 通路。此外，IGF2BP3 增加了 CRC 细胞对 EGFR 靶向抗体西妥昔单抗的耐药性。综上所述，我们的研究结果表明 IGF2BP3 是 CRC 的功能性临床致癌基因。因此，靶向 IGF2BP3 和 m6A 修饰可能为 CRC 患者提供合理的治疗靶点。
