microRNA-21-5p from M2 macrophage-derived extracellular vesicles promotes the differentiation and activity of pancreatic cancer stem cells by mediating KLF3.
microRNA-21-5p from M2 macrophage-derived extracellular vesicles promotes the differentiation and activity of pancreatic cancer stem cells by mediating KLF3.
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DOI：
10.1007/s10565-021-09597-x
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发表时间：
2022-08
影响因子：
6.1
通讯作者：
中科院分区：
文献类型：
--
作者：
鉴于肿瘤相关巨噬细胞来源的细胞外囊泡（EVs）可归因于肿瘤侵袭性，本研究拟通过传递microRNA (miR)-21-5p来解码M2巨噬细胞来源的EVs在胰腺癌（PaCa）干细胞分化和活性中的机制。诱导极化的M2巨噬细胞，收集并鉴定ev。检测M2巨噬细胞源性EVs中miR-21-5p的表达。细胞分选后，CD24+CD44+EpCAM+干细胞与M2巨噬细胞共培养，miR-21-5p上调或下调。研究了M2巨噬细胞来源的ev和miR-21-5p对Nanog/ octmer结合转录因子4 （Oct4）表达、球体形成、集落形成、侵袭和迁移能力、细胞凋亡和体内致瘤能力的影响。检测kr<s:1> ppel样因子3 （KLF3）的表达及其与miR-21-5p的相互作用。M2巨噬细胞源性EVs促进PaCa干细胞的分化和活性。miR-21a-5p在M2巨噬细胞源性EVs中上调。M2巨噬细胞源性EVs中miR-21a-5p的下调抑制了Nanog/Oct4的表达，损害了PaCa干细胞在体外的成球、集落形成、侵袭、迁移和抗凋亡能力以及体内的致瘤能力。miR-21-5p靶向KLF3介导PaCa干细胞的分化和活性，而KLF3在PaCa干细胞中下调。这项工作解释了M2巨噬细胞来源的外泌体miR-21a-5p通过靶向KLF3刺激PaCa干细胞的分化和活性，为减弱PaCa干性铺平了新的途径。
Given the fact that tumor-associated macrophage-derived extracellular vesicles (EVs) are attributable to tumor aggressiveness, this research intends to decode the mechanism of M2 macrophage-derived EVs in the differentiation and activities of pancreatic cancer (PaCa) stem cells via delivering microRNA (miR)-21-5p. Polarized M2 macrophages were induced, from which EVs were collected and identified. miR-21-5p expression in M2 macrophage-derived EVs was tested. After cell sorting, CD24+CD44+EpCAM+ stem cells were co-cultured with M2 macrophages, in which miR-21-5p was upregulated or downregulated. The effects of M2 macrophage-derived EVs and miR-21-5p on Nanog/octamer-binding transcription factor 4 (Oct4) expression, sphere formation, colony formation, invasion and migration capacities, apoptosis, and in vivo tumorigenic ability were examined. Krüppel-like factor 3 (KLF3) expression and its interaction with miR-21-5p were determined. M2 macrophage-derived EVs promoted PaCa stem cell differentiation and activities. miR-21a-5p was upregulated in M2 macrophage-derived EVs. miR-21a-5p downregulation in M2 macrophage-derived EVs inhibited Nanog/Oct4 expression and impaired sphere-forming, colony-forming, invasion, migration, and anti-apoptosis abilities of PaCa stem cells in vitro and tumorigenic ability in vivo. miR-21-5p targeted KLF3 to mediate the differentiation and activities of PaCa stem cells, and KLF3 was downregulated in PaCa stem cells. This work explains that M2 macrophage-derived exosomal miR-21a-5p stimulates differentiation and activity of PaCa stem cells via targeting KLF3, paving a novel way for attenuating PaCa stemness.
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影响因子：
4.3
作者：
Becerra-Diaz, Mireya;Lerner, Andrew D.;Yu, Diana H.;Thiboutot, Jeffrey P.;Liu, Mark C.;Yarmus, Lonny B.;Bose, Sonali;Heller, Nicola M.
通讯作者：
Heller, Nicola M.
影响因子：
5.6
作者：
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影响因子：
10.9
作者：
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通讯作者：
Hylander BL
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影响因子：
7.5
作者：
Li, Kejia;Ning, Tong;Ge, Zigang
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Ge, Zigang
影响因子：
11.5
作者：
Phu Hung Nguyen;Giraud, Julie;Varon, Christine
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Varon, Christine