MicroRNA-15a Carried by Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibits the Immune Evasion of Colorectal Cancer Cells by Regulating the KDM4B/HOXC4/PD-L1 Axis.
MicroRNA-15a Carried by Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibits the Immune Evasion of Colorectal Cancer Cells by Regulating the KDM4B/HOXC4/PD-L1 Axis.
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间充质干细胞来源的细胞外囊泡携带的microRNA-15 a通过调节KDM 4 B/HOXC 4/PD-L1轴抑制结直肠癌细胞的免疫逃避
DOI：
10.3389/fcell.2021.629893
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zhao C
中科院分区：
文献类型：
--
作者：
Liu L;Yu T;Jin Y;Mai W;Zhou J;Zhao C
microRNA-15 a（miR-15 a）与自身免疫的相关性已有报道。在此，我们打算探讨miR-15 a穿梭脂肪间充质干细胞（adMSCs）衍生的细胞外囊泡（Evs）在结直肠癌（CRC）中的潜在作用。最初，用干扰素γ（IFN-γ）处理CRC细胞以通过转录组测序筛选差异表达的基因。在与20 μM adMSC衍生的Ev共培养24小时后，评估CRC细胞活力、迁移、侵袭和凋亡。在确定组蛋白赖氨酸脱甲基酶4 B（KDM 4 B）为靶基因后，通过生物信息学网站预测其调控miRNA，并通过双荧光素酶和RNA pull-down实验进行验证。有趣的是，KDM 4 B下调同源异型盒C4（HOXC 4）的表达，而HOXC 4与程序性死亡配体1（PD-L1）的启动子序列结合。因此，我们进行了拯救实验来研究KDM 4 B和HOXC 4的作用。最后，我们通过体内致瘤实验评估了adMSCs对CRC细胞生长和免疫逃避的影响。过表达miR-15 a的AdMSC衍生的Evs抑制了CRC细胞的增殖、迁移和侵袭，同时通过下调KDM 4 B促进了CRC细胞的凋亡。这些体内发现在体外对CRC免疫逃避重现。总的来说，过表达miR-15 a的adMSC衍生的Ev通过KDM 4 B/HOXC 4/PD-L1轴限制了CRC的免疫逃避。
The relevance of microRNA-15a (miR-15a) to autoimmunity has been reported. Herein, we intended to probe the potential roles of miR-15a shuttled by adipose-derived mesenchymal stem cells (adMSCs)-derived extracellular vesicles (Evs) in colorectal cancer (CRC). Initially, CRC cells were treated with interferon gamma (IFN-γ) to screen out differentially expressed genes by transcriptome sequencing. Following a 24-h co-culture with 20 μM adMSCs-derived Evs, CRC cell viability, migration, invasion, and apoptosis were assessed. After the determination of histone lysine demethylase 4B (KDM4B) as our target, its regulatory miRNA was predicted by the bioinformatics websites and verified by dual-luciferase and RNA pull-down assays. Intriguingly, KDM4B downregulated homeobox C4 (HOXC4) expression, while HOXC4 bound to the promoter sequence of programmed death-ligand 1 (PD-L1). Thus, we conducted rescue experiments to study the role of KDM4B and HOXC4. Finally, we evaluated the effects of adMSCs on CRC cell growth and immune evasion through in vivo tumorigenesis experiments. AdMSCs-derived Evs overexpressing miR-15a repressed proliferation, migration, and invasion, while it promoted the apoptosis of CRC cells via downregulation of KDM4B. These in vivo findings were reproduced in vitro on CRC immune evasion. Collectively, adMSCs-derived Evs overexpressing miR-15a restricted the immune evasion of CRC via the KDM4B/HOXC4/PD-L1 axis.
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影响因子：
8
作者：
Wilson C;Qiu L;Hong Y;Karnik T;Tadros G;Mau B;Ma T;Mu Y;New J;Louie RJ;Gunewardena S;Godwin AK;Tawfik OW;Chien J;Roby KF;Krieg AJ
通讯作者：
Krieg AJ
影响因子：
2.7
作者：
Cui, Feng;Qu, Di;Nan, Kejun
通讯作者：
Nan, Kejun
MiR-15a 通过靶向 CXCL10 导致重症肌无力异常免疫反应
影响因子：
8.6
作者：
Liu, Xiao-Fang;Wang, Run-Qi;Yang, Huan
通讯作者：
Yang, Huan
影响因子：
5.2
作者：
Huang, Kevin Chih-Yang;Chiang, Shu-Fen;Chao, K. S. Clifford
通讯作者：
Chao, K. S. Clifford
影响因子：
8.8
作者：
Abiko, K.;Matsumura, N.;Hamanishi, J.;Horikawa, N.;Murakami, R.;Yamaguchi, K.;Yoshioka, Y.;Baba, T.;Konishi, I.;Mandai, M.
通讯作者：
Mandai, M.