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骨间充质干细胞来源的细胞外囊泡将 microRNA-206 转运至骨肉瘤细胞中，并靶向 NRSN2 阻断 ERK1/2-Bcl-xL 信号通路。

Extracellular vesicles from bone mesenchymal stem cells transport microRNA-206 into osteosarcoma cells and target NRSN2 to block the ERK1/2-Bcl-xL signaling pathway.

机构信息

Orthopedic Center, First People's Hospital of Kashgar, Xinjiang.

出版信息

Eur J Histochem. 2022 Jun 22;66(3):3394. doi: 10.4081/ejh.2022.3394.

DOI:10.4081/ejh.2022.3394
PMID:35730574
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9251612/
Abstract

Osteosarcoma (OS) is a kind of malignant tumor originating from mesenchymal tissue Bone mesenchymal stem cells-derived extracellular vesicles (BMSCs-EVs) can play important roles in OS. This study investigated the mechanism of BMSCs-EVs on OS. BMSC surface antigens and adipogenic and osteogenic differentiation were detected by flow cytometry, and oil red O and alizarin red staining. EVs were isolated from BMSCs by differential centrifugation and identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot (WB). miR-206 and neurensin-2 (NRSN2) levels in human osteoblast hFOB 1.19 or OS cells (143B, MG-63, Saos2, HOS) were detected by RT-qPCR. Human OS cells with lower miR-206 levels were selected and treated with BMSCs-EVs or pSUPER-NRSN2. The uptake of EVs by 143B cells, cell proliferation, apoptosis, invasion, and migration were detected by immunofluorescence, 5-ethynyl-2'-deoxyuridine (EdU) and colony formation assays, flow cytometry, scratch test, and transwell assays. The binding sites between miR-206 and NRSN2 were predicted by Starbase database and verified by dual-luciferase assay. The OS xenograft model was established and treated by BMSCs-EVs. Tumor growth rate and volume, cell proliferation, and p-ERK1/2, ERK1/2, and Bcl-xL levels were detected by vernier caliper, immunohistochemistry, and WB. BMSCs-EVs were successfully extracted. miR-206 was diminished and NRSN2 was promoted in OS cells. BMSCs-EVs inhibited proliferation, migration, and invasion, and promoted apoptosis of OS cells. BMSCs-EVs carried miR-206 into OS cells. Inhibition of miR-206 in EVs partially reversed the inhibitory effect of EVs on malignant behaviors of OS cells. miR-206 targeted NRSN2. Overexpression of NRSN2 reversed the inhibitory effect of EVs on OS cells. NRSN2 activated the ERK1/2-Bcl-xL pathway. BMSC-EVs inhibited OS growth in vivo. In summary, BMSC-EVs targeted NRSN2 and inhibited the ERK1/2-Bcl-xL pathway by carrying miR-206 into OS cells, thus inhibiting OS progression.

摘要

骨肉瘤（OS）是一种起源于间充质组织的恶性肿瘤。骨髓间充质干细胞衍生的细胞外囊泡（BMSCs-EVs）在 OS 中发挥重要作用。本研究探讨了 BMSCs-EVs 对 OS 的作用机制。通过流式细胞术、油红 O 和茜素红染色检测 BMSC 表面抗原和脂肪和成骨分化。通过差速离心从 BMSCs 中分离 EVs，并通过透射电子显微镜、纳米颗粒跟踪分析和 Western blot（WB）进行鉴定。通过 RT-qPCR 检测人成骨细胞 hFOB 1.19 或 OS 细胞（143B、MG-63、Saos2、HOS）中 miR-206 和神经内肽-2（NRSN2）的水平。选择 miR-206 水平较低的人 OS 细胞，并用 BMSCs-EVs 或 pSUPER-NRSN2 处理。通过免疫荧光、5-乙炔基-2'-脱氧尿苷（EdU）和集落形成实验、流式细胞术、划痕试验和 Transwell 试验检测 143B 细胞摄取 EVs、细胞增殖、凋亡、侵袭和迁移。通过 Starbase 数据库预测 miR-206 和 NRSN2 之间的结合位点，并通过双荧光素酶报告基因实验验证。建立 OS 异种移植模型，并用 BMSCs-EVs 处理。通过游标卡尺、免疫组织化学和 WB 检测肿瘤生长速度和体积、细胞增殖以及 p-ERK1/2、ERK1/2 和 Bcl-xL 水平。成功提取 BMSCs-EVs。OS 细胞中 miR-206 减少，NRSN2 增加。BMSCs-EVs 抑制 OS 细胞的增殖、迁移和侵袭，并促进其凋亡。BMSCs-EVs 将 miR-206 带入 OS 细胞。EVs 中 miR-206 的抑制部分逆转了 EVs 对 OS 细胞恶性行为的抑制作用。miR-206 靶向 NRSN2。NRSN2 的过表达逆转了 EVs 对 OS 细胞的抑制作用。NRSN2 激活了 ERK1/2-Bcl-xL 通路。BMSC-EVs 抑制体内 OS 生长。综上所述，BMSCs-EVs 通过携带 miR-206 进入 OS 细胞靶向 NRSN2，并抑制 ERK1/2-Bcl-xL 通路，从而抑制 OS 进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/e4db68f7ebdb/ejh-66-3-3394-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/960c89054558/ejh-66-3-3394-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/69170b44ce9f/ejh-66-3-3394-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/63fd20893947/ejh-66-3-3394-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/2b1a69732a85/ejh-66-3-3394-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/b3c362ce3699/ejh-66-3-3394-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/4431cb80a9a0/ejh-66-3-3394-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/c667cacbeea1/ejh-66-3-3394-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/e4db68f7ebdb/ejh-66-3-3394-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/960c89054558/ejh-66-3-3394-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/69170b44ce9f/ejh-66-3-3394-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/63fd20893947/ejh-66-3-3394-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/2b1a69732a85/ejh-66-3-3394-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/b3c362ce3699/ejh-66-3-3394-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/4431cb80a9a0/ejh-66-3-3394-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/c667cacbeea1/ejh-66-3-3394-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e31/9251612/e4db68f7ebdb/ejh-66-3-3394-g008.jpg

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[3]
Apoptotic Vesicles Derived from Dental Pulp Stem Cells Promote Bone Formation through the ERK1/2 Signaling Pathway.

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[4]
Extracellular vesicles in tumorigenesis, metastasis, chemotherapy resistance and intercellular communication in osteosarcoma.

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[5]
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[6]
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[7]
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本文引用的文献

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Bone Marrow Mesenchymal Stem Cells-Derived Extracellular Vesicles Promote Proliferation, Invasion and Migration of Osteosarcoma Cells via the lncRNA MALAT1/miR-143/NRSN2/Wnt/β-Catenin Axis.

Onco Targets Ther. 2021-2-2

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