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急性髓系白血病细胞来源的含 microRNA-1246 的细胞外囊泡通过 LRIG1 介导的 STAT3 通路促进白血病干细胞的存活。

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

机构信息

Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Department 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.

出版信息

Aging (Albany NY). 2021 Apr 23;13(10):13644-13662. doi: 10.18632/aging.202893.

DOI:10.18632/aging.202893
PMID:33893245
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8202884/
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 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.

摘要

癌细胞分泌的细胞外囊泡 (EVs) 已成为局部和远处微环境中细胞间通讯的重要介质。我们最初的 GEO 数据库分析确定，急性髓系白血病 (AML) 细胞衍生的 EVs 中存在差异表达的 microRNA-1246 (miR-1246)。因此，本研究旨在研究 AML 衍生的 EV 包装的 miR-1246 在白血病干细胞 (LSCs) 生物学活性中的作用。使用双荧光素酶报告基因检测验证了 miR-1246 与 LRIG1 之间的预测结合。然后，在 LSCs 中进行了增益和缺失功能测定，其中将 LSCs 与 AML 细胞衍生的 EV 共培养，以表征含有 miR-1246 的 EV、miR-1246、LRIG1 和 STAT3 通路在 LSCs 中的作用。我们的研究结果表明，在 AML 细胞衍生的 EVs 中，miR-1246 高表达，并直接靶向 LRIG1 以激活 STAT3 通路。发现 miR-1246 抑制剂或 EV 包裹的 miR-1246 抑制剂通过上调 LRIG1 使 STAT3 通路失活，从而抑制 LSCs 的活力和集落形成能力，但促进 LSCs 的凋亡和分化。此外，携带 miR-1246 抑制剂的 AML 细胞衍生 EVs 对 LSCs 的抑制作用通过实验得到了证实。总之，我们的研究结果表明，抑制含有 miR-1246 抑制剂的 AML 细胞衍生 EVs 通过失活 LRIG1 介导的 STAT3 通路改变 LSCs 的存活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46f5/8202884/15d53fb96c64/aging-13-202893-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46f5/8202884/9837e513c1f4/aging-13-202893-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46f5/8202884/67c7fe916323/aging-13-202893-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46f5/8202884/15d53fb96c64/aging-13-202893-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46f5/8202884/9837e513c1f4/aging-13-202893-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46f5/8202884/67c7fe916323/aging-13-202893-g007.jpg
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