2. Academic Validation
  3. MicroRNA-143 acts as a tumor suppressor through Musashi-2/DLL1/Notch1 and Musashi-2/Snail1/MMPs axes in acute myeloid leukemia

MicroRNA-143 acts as a tumor suppressor through Musashi-2/DLL1/Notch1 and Musashi-2/Snail1/MMPs axes in acute myeloid leukemia

  • J Transl Med. 2023 May 6;21(1):309. doi: 10.1186/s12967-023-04106-6.
Fanfan Li # 1 2 3,  Yixiang Han # 2 3 4,  Rongrong Chen # 1 2 3,  Yinyan Jiang 1 2 3,  Cheng Chen 1 2 3,  Xiaofang Wang 1 2 3,  Jifan Zhou 1 2 3,  Qingqing Xu 5,  Songfu Jiang 1 2 3,  Si Zhang 6,  Kang Yu 7 8 9,  Shenghui Zhang 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China.
  • 2 Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3 Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China.
  • 4 Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 5 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 6 Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 7 Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China. yukang62@126.com.
  • 8 Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China. yukang62@126.com.
  • 9 Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China. yukang62@126.com.
  • 10 Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China. zhangshenghui@wmu.edu.cn.
  • 11 Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China. zhangshenghui@wmu.edu.cn.
  • 12 Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China. zhangshenghui@wmu.edu.cn.
  • 13 Laboratory Animal Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. zhangshenghui@wmu.edu.cn.
  • # Contributed equally.
PMID: 37149661 DOI: 10.1186/s12967-023-04106-6
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Acute myeloid leukemia; DLL1; Musashi-2; Snail1; microRNA-143.

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