转移仍然是鼻咽癌（NPC）患者治疗失败的主要原因，其中Notch信号的持续激活起着关键作用。 N6-甲基腺苷 (m6A) 介导的转录后调节参与微调 Notch 信号输出；然而，NPC 转移的转录后机制仍知之甚少。在本研究中，我们报告胰岛素样生长因子 2 mRNA 结合蛋白 3 (IGF2BP3) 作为 NPC 中的关键 m6A 读取器。 IGF2BP3 表达在转移性鼻咽癌中显着上调，并且与鼻咽癌患者的不良预后相关。在体外和体内，IGF2BP3过表达促进，而IGF2BP3下调抑制肿瘤转移和鼻咽癌细胞的干性表型。从机制上讲，IGF2BP3通过以m6A依赖性方式抑制CCR4-NOT复合物介导的去腺苷化来维持NOTCH3 mRNA的稳定性，从而维持Notch3信号激活并增加干性相关下游基因的转录，最终促进肿瘤转移。我们的研究结果强调了 IGF2BP3/Notch3 轴的促转移功能，并揭示了 IGF2BP3 在 NOTCH3 转录后调节中的精确作用，表明 IGF2BP3 作为一种新型预后生物标志物和鼻咽癌转移的潜在治疗靶点。© 2023。作者（ s）。

Metastasis remains the major cause of treatment failure in patients with nasopharyngeal carcinoma (NPC), in which sustained activation of the Notch signaling plays a critical role. N6-Methyladenosine (m6A)-mediated post-transcriptional regulation is involved in fine-tuning the Notch signaling output; however, the post-transcriptional mechanisms underlying NPC metastasis remain poorly understood. In the present study, we report that insulin-like growth factor 2 mRNA-binding proteins 3 (IGF2BP3) serves as a key m6A reader in NPC. IGF2BP3 expression was significantly upregulated in metastatic NPC and correlated with poor prognosis in patients with NPC. IGF2BP3 overexpression promoted, while IGF2BP3 downregulation inhibited tumor metastasis and the stemness phenotype of NPC cells in vitro and in vivo. Mechanistically, IGF2BP3 maintains NOTCH3 mRNA stability via suppression of CCR4-NOT complex-mediated deadenylation in an m6A-dependent manner, which sustains Notch3 signaling activation and increases the transcription of stemness-associated downstream genes, eventually promoting tumor metastasis. Our findings highlight the pro-metastatic function of the IGF2BP3/Notch3 axis and revealed the precise role of IGF2BP3 in post-transcriptional regulation of NOTCH3, suggesting IGF2BP3 as a novel prognostic biomarker and potential therapeutic target in NPC metastasis.© 2023. The Author(s).