N6-甲基腺苷(m6A) RNA 甲基化及其相关的 RNA 结合蛋白胰岛素样生长因子 2 mRNA 结合蛋白1(IGF2BP1) 参与了肿瘤的发生和进展。本研究探讨了 IGF2BP1 在肝内胆管癌(iCCA) 中的生物功能和临床意义。我们发现，IGF2BP1 的表达受到 H3K27 乙酰化富集其启动子的影响，其与生存率和临床病理特征呈正相关。增-减功能实验表明，IGF2BP1 过表达(沉默) 在体内和体外都能增强(减弱) iCCA 的生长和转移。机制上，IGF2BP1 不仅调控 c-Myc/p16 轴促进 iCCA 生长并抑制细胞衰老，还激活 ZIC2/PAK4/AKT/MMP2 轴诱导肿瘤转移。更重要的是，最近发现的 IGF2BP1 抑制剂 BTYNB，在患者来源的异种移植模型中表现出有希望的抗肿瘤疗效，而 IGF2BP1 条件性敲除(cKO) 则减轻了肿瘤负担。这些结果证明了 IGF2BP1 在 iCCA 进展中的关键作用，强调了 IGF2BP1 作为iCCA 潜在的治疗靶点。Copyright © 2023 Elsevier B.V. All rights reserved.

N6-methyladenosine (m6A) RNA methylation and its associated RNA-binding protein insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) are involved in tumor initiation and progression. Here, we explored the biological function and clinical significance of IGF2BP1 in intrahepatic cholangiocarcinoma (iCCA). We found that IGF2BP1 expression was upregulated by H3K27 acetylation enrichment of its promoter, which positively correlated with poor clinicopathological characteristics and survival. Gain- and loss-of-function experiments showed that IGF2BP1 overexpression (knockdown) enhanced (attenuated) iCCA growth and metastasis in vitro and in vivo. Mechanistically, IGF2BP1 not only regulated the c-Myc/p16 axis to promote iCCA growth and inhibit senescence, but also activated the ZIC2/PAK4/AKT/MMP2 axis to induce tumor metastasis. More importantly, BTYNB, a recently identified IGF2BP1 inhibitor, exerted promising anti-tumor efficacy in a patient-derived xenograft (PDX) model, and IGF2BP1 conditional knockout (cKO) reduced the tumor burden. These results demonstrate the crucial role of IGF2BP1 in iCCA progression via m6A-dependent modification, highlighting IGF2BP1 as a potential therapeutic target in iCCA.Copyright © 2023 Elsevier B.V. All rights reserved.