Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China.
Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China.
J Transl Med. 2023 May 6;21(1):309. doi: 10.1186/s12967-023-04106-6.
The previous studies have revealed that abnormal RNA-binding protein Musashi-2 (MSI2) expression is associated with cancer progression through post-transcriptional mechanisms, however mechanistic details of this regulation in acute myeloid leukemia (AML) still remain unclear. Our study aimed to explore the relationship between microRNA-143 (miR-143) and MSI2 and to clarify their clinical significance, biological function and mechanism.
Abnormal expression of miR-143 and MSI2 were evaluated in bone marrow samples from AML patients by quantitative real time-PCR. Effects of miR-143 on regulating MSI2 expression were investigated using luciferase reporter assay. Functional roles of MSI2 and miR-143 on AML cell proliferation and migration were determined by CCK-8 assay, colony formation, and transwell assays in vitro and in mouse subcutaneous xenograft and orthotopic transplantation models in vivo. RNA immunoprecipitation, RNA stability measurement and Western blotting were performed to assess the effects of MSI2 on AML.
We found that MSI2 was significantly overexpressed in AML and exerted its role of promoting AML cell growth by targeting DLL1 and thereby activating Notch signaling pathway. Moreover, we found that MSI2 bound to Snail1 transcript and inhibited its degradation, which in turn upregulated the expression of matrix metalloproteinases. We also found that MSI2 targeting miR-143 is downregulated in AML. In the AML xenograft mouse model, overexpression of MSI2 recapitulated its leukemia-promoting effects, and overexpression of miR-143 partially attenuated tumor growth and prevented metastasis. Notably, low expression of miR-143, and high expression of MSI2 were associated with poor prognosis in AML patients.
Our data demonstrate that MSI2 exerts its malignant properties via DLL1/Notch1 cascade and the Snail1/MMPs axes in AML, and upregulation of miR-143 may be a potential therapeutic approach for AML.
先前的研究表明，异常 RNA 结合蛋白 Musashi-2（MSI2）的表达通过转录后机制与癌症进展有关，然而急性髓系白血病（AML）中这种调节的机制细节仍不清楚。我们的研究旨在探讨 microRNA-143（miR-143）与 MSI2 之间的关系，并阐明它们的临床意义、生物学功能和机制。
通过定量实时 PCR 评估 AML 患者骨髓样本中 miR-143 和 MSI2 的异常表达。使用荧光素酶报告基因检测研究 miR-143 对调节 MSI2 表达的影响。体外 CCK-8 测定、集落形成和 Transwell 测定以及体内小鼠皮下异种移植和原位移植模型中，确定 MSI2 和 miR-143 对 AML 细胞增殖和迁移的功能作用。进行 RNA 免疫沉淀、RNA 稳定性测量和 Western blot 以评估 MSI2 对 AML 的影响。
我们发现 MSI2 在 AML 中显著过表达，并通过靶向 DLL1 从而激活 Notch 信号通路发挥其促进 AML 细胞生长的作用。此外，我们发现 MSI2 与 Snail1 转录本结合并抑制其降解，从而上调基质金属蛋白酶的表达。我们还发现，MSI2 靶向的 miR-143 在 AML 中下调。在 AML 异种移植小鼠模型中，过表达 MSI2 再现了其促进白血病的作用，过表达 miR-143 部分减弱了肿瘤生长并防止了转移。值得注意的是，miR-143 低表达和 MSI2 高表达与 AML 患者的不良预后相关。
我们的数据表明，MSI2 通过 DLL1/Notch1 级联和 Snail1/MMPs 轴在 AML 中发挥其恶性特性，上调 miR-143 可能是 AML 的一种潜在治疗方法。
