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Research Paper|Volume 13, Issue 10|pp 13644—13662

microRNA-1246-containing extracellular vesicles from acute myeloid leukemia cells promote the survival of leukemia stem cells via the LRIG1-meditated STAT3 pathway

Lijuan Chen1, Zhi Guo2, Yongming Zhou3, Jian Ni4, Jianhua Zhu5, Xu Fan6, Xuexing Chen7, Yiling Liu7, Ziping Li7, Hao Zhou7
  • 1Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
  • 2Department of Hematology and Oncology, National Cancer Center/National Clinical Research Cancer for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
  • 3Department of Hematology, The Affiliated Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430064, China
  • 4Department of Oncology Clinical Pharmacy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
  • 5Laboratory of Clinical Immunology, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
  • 6Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center for Digestive Diseases, Beijing 100050, China
  • 7Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Received: February 5, 2020Accepted: July 14, 2020Published: April 23, 2021
https://doi.org/10.18632/aging.202893

Copyright: © 2021 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Cancer cells-secreted extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in local and distant microenvironment. Our initial GEO database analysis identified the presence of differentially-expressed microRNA-1246 (miR-1246) in acute myeloid leukemia (AML) cell-derived EVs. Consequently, the current study set out to investigate the role of AML-derived EVs-packaged miR-1246 in leukemia stem cells (LSCs) bioactivities. The predicted binding between miR-1246 and LRIG1 was verified using dual luciferase reporter assay. Then, gain- and loss-of-function assays were performed in LSCs, where LSCs were co-cultured with AML cell-derived EVs to characterize the effects of miR-1246-containing EVs, miR-1246, LRIG1 and STAT3 pathway in LSCs. Our findings revealed, in AML cell-derived EVs, miR-1246 was highly-expressed and directly-targeted LRIG1 to activate the STAT3 pathway. MiR-1246 inhibitor or EV-encapsulated miR-1246 inhibitor was found to suppress the viability and colony formation abilities but promoted the apoptosis and differentiation of LSCs through inactivation of STAT3 pathway by up-regulating LRIG1. In addition, the inhibitory effects of AML cell-derived EVs carrying miR-1246 inhibitor on LSCs were substantiated by in vivo experiments. Collectively, our findings reveal that the repression of AML cell-derived EVs containing miR-1246 inhibitor alters the survival of LSCs by inactivating the LRIG1-mediated STAT3 pathway.