IGF2BP3促进结直肠癌的进展，并以一种m6A依赖机制通过稳定EGFR mRNA介导西妥昔单抗耐药性。
IGF2BP3 promotes the progression of colorectal cancer and mediates cetuximab resistance by stabilizing EGFR mRNA in an m6A-dependent manner.
发表日期：2023 Sep 01
作者：
Li-Jie Chen, Hui-Ye Liu, Zhi-Yuan Xiao, Ting Qiu, Dan Zhang, Ling-Jie Zhang, Fang-Yi Han, Guo-Jun Chen, Xue-Mei Xu, Jiong-Hua Zhu, Yan-Qing Ding, Shu-Yang Wang, Ya-Ping Ye, Hong-Li Jiao
来源：
Cell Death & Disease
摘要：
胰岛素样生长因子2mRNA结合蛋白3(IGF2BP3)是一种与肿瘤发生和进展相关的RNA结合蛋白。然而，IGF2BP3在结直肠癌(CRC)肿瘤发生、进展和药物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的升高水平预测预后不良。在功能上，IGF2BP3增强了CRC的体外和体内肿瘤发生和进展。机制上，IGF2BP3通过与METTL14合作，以N6-甲基腺苷(m6A)依赖的方式促进表皮生长因子受体(EGFR)的mRNA稳定性和翻译，并进一步激活EGFR通路，从而成为一个读者。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，我们的结果证明IGF2BP3是CRC的功能性和临床上的癌基因。因此，针对IGF2BP3和m6A修饰可能为CRC患者提供合理的治疗靶点。© 2023. 作者。
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 (m6A)-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 m6A modification may therefore offer rational therapeutic targets for patients with CRC.© 2023. The Author(s).