The major function of Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is to regulate cell metabolism. However, emerging evidence indicates that IGF2BP2 plays a role in cancer, but the underlying mechanism is largely unknown. Here we showed that upregulation of IGF2BP2 is associated with poor outcomes of pancreatic cancer patients and suppression of IGF2BP2 inhibits cell proliferation. We further showed that IGF2BP2 regulates lncRNA DANCR. Ectopic expression IGF2BP2 enhances, whereas knockdown (KD) or knockout (KO) of IGF2BP2 suppresses DANCR expression. Moreover, in vivo RNA precipitation and reciprocal RNA immunoprecipitation revealed that IGF2BP2 interacts with DANCR. DANCR promotes cell proliferation and stemness-like properties. Experiments with xenograft models revealed that while ectopic expression of DANCR promotes, DANCR KO suppresses tumor growth. Mechanistically, DANCR is modified at N6-methyladenosine (m6A) and mutagenesis assay identified that adenosine at 664 of DANCR is critical to the interaction between IGF2BP2 and DANCR where IGF2BP2 serves a reader for m6A modified DANCR and stabilizes DANCR RNA. Together, these results suggest that DANCR is a novel target for IGF2BP2 through m6A modification, and IGF2BP2 and DANCR work together to promote cancer stemness-like properties and pancreatic cancer pathogenesis.

中文翻译：

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IGF2BP2 通过充当 N6-甲基腺苷读取器来调节 DANCR。

胰岛素样生长因子 2 mRNA 结合蛋白 2 (IGF2BP2) 的主要功能是调节细胞代谢。然而，新出现的证据表明 IGF2BP2 在癌症中发挥作用，但其潜在机制尚不清楚。在这里，我们发现 IGF2BP2 的上调与胰腺癌患者的不良预后相关，并且 IGF2BP2 的抑制会抑制细胞增殖。我们进一步表明 IGF2BP2 调节 lncRNA DANCR。IGF2BP2 的异位表达增强，而 IGF2BP2 的敲除 (KD) 或敲除 (KO) 抑制 DANCR 表达。此外，体内RNA沉淀和相互RNA免疫沉淀揭示IGF2BP2与DANCR相互作用。DANCR 促进细胞增殖和干细胞样特性。异种移植模型实验表明，虽然 DANCR 的异位表达促进肿瘤生长，但 DANCR KO 却抑制肿瘤生长。从机制上讲，DANCR 在 N6-甲基腺苷 (m6A) 处被修饰，诱变分析发现 DANCR 664 处的腺苷对于 IGF2BP2 和 DANCR 之间的相互作用至关重要，其中 IGF2BP2 充当 m6A 修饰的 DANCR 的读取器并稳定 DANCR RNA。总之，这些结果表明 DANCR 是通过 m6A 修饰的 IGF2BP2 的新靶点，并且 IGF2BP2 和 DANCR 共同作用促进癌症干性样特性和胰腺癌发病机制。