微RNA-887-3p能抑制大鼠椎间盘纤维环细胞中 MDM4表达和细胞增殖并促进细胞凋亡

doi:10.12300/j.issn.1674-5817.2024.003

实验动物与比较医学 ›› 2024, Vol. 44 ›› Issue (3): 270-278.DOI: 10.12300/j.issn.1674-5817.2024.003

微RNA-887-3p能抑制大鼠椎间盘纤维环细胞中 MDM4表达和细胞增殖并促进细胞凋亡

朱晓雨, 袁韩涛, 李四波()()

上海中医药大学附属第七人民医院脊柱外科, 上海 200137

收稿日期:2024-01-05 修回日期:2024-05-10 出版日期:2024-07-06 发布日期:2024-06-25
通讯作者: 李四波（1978—），男，博士，副主任医师，从事脊柱退行性病变临床与实验研究。E-mail： 13761603358@163.com。ORCID： 0000-0002-3822-1509
作者简介:朱晓雨（1998—），女，硕士研究生，从事脊柱退行性病变研究。E-mail: 1254402429@qq.com
基金资助:
上海市浦东新区科技发展基金-民生科研专项“椎间盘纤维环细胞中hsa-miR-887-3p在凋亡中的作用及复合胶原蛋白海绵修复大鼠纤维环损伤的研究”(PKJ2019-Y18);上海市浦东新区卫生健康委学科带头人培养计划-李四波(PWRd2019-10);浦东新区中央财政支持中医药传承创新发展示范试点项目“石印玉全国名中医传承工作室”(YC-2023-0120);“中医高峰学科（中西医结合骨伤科）”(YC-2023-0601);财政部国家中医药管理局医疗服务与保障能力提升补助资金（重点科室部分）项目“中西医协同重点科室建设"(沪卫中管便函〔2023〕46号)

MicroRNA-887-3p Inhibited MDM4 Expression and Proliferation but Promoted Apoptosis of Intervertebral Disc Annulus Fibrosus Cells in Rats

Xiaoyu ZHU, Hantao YUAN, Sibo LI()()

Department of Spinal Surgery, Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China

Received:2024-01-05 Revised:2024-05-10 Published:2024-06-25 Online:2024-07-06
Contact: LI Sibo (ORCID: 0000-0002-3822-1509), E-mail: 13761603358@163.com

摘要/Abstract

摘要：

目的探讨微RNA（microRNA，miRNA或miR）-887-3p对大鼠椎间盘纤维环细胞增殖和凋亡的影响及其潜在的分子机制。方法取8周龄SPF级雄性SD大鼠的纤维环组织，离心制备并鉴定纤维环细胞。实验随机分为4组：正常组（Normal group）是不做任何处理的原代纤维环细胞；对照组（Control group）用10 ng/mL白细胞介素-1β（interleukin-1β，IL-1β）处理纤维环细胞24 h，形成退变细胞模型；干扰组（miR-887-3p inhibitor）是在对照组的基础上用Lipo3000转染miR-887-3p 抑制子；过表达组（miR-887-3p mimics）是在对照组的基础上用Lipo3000转染miR-887-3p模拟物。采用CCK-8法检测各组细胞活力；流式细胞术检测各组细胞凋亡率；实时荧光定量PCR法检测miR-887-3p和鼠双微体4（murine double minute 4，MDM4）mRNA的表达；蛋白质印迹法检测MDM4、Bcl-2和Caspase-3的蛋白表达水平。结果免疫荧光染色法鉴定分离培养的细胞发现，大鼠椎间盘纤维环细胞中Collagen I的阳性率在90%以上，提示纤维环细胞纯度大于90%。实时荧光定量PCR结果显示，利用IL-1β构建纤维环退变细胞模型后，miR-887-3p表达水平与正常组相比显著上升（P<0.001）；与对照组相比，转染miR-887-3p抑制子后，miR-887-3p表达水平显著下降（P<0.001）。CCK-8法检测结果表明，与正常组相比，对照组细胞活力显著下降（P<0.001）；与对照组相比，抑制miR-887-3p的表达后，细胞增殖能力显著增强；miR-887-3p过表达后，细胞增殖能力显著下降。流式细胞仪检测结果表明，与正常组相比，对照组的细胞凋亡率显著增加（P<0.001）；与对照组相比，miR-887-3p干扰组的细胞凋亡率显著降低（P<0.001），miR-887-3p过表达组的细胞凋亡率显著增加（P<0.001）。蛋白质印迹法检测结果发现，与正常组相比，对照组中Bcl-2的表达水平显著降低（P<0.001），Caspase-3的表达水平显著升高（P<0.001）；与对照组相比，miR-887-3p干扰组中Bcl-2和MDM4表达水平显著升高（P<0.01），Caspase-3的表达水平显著降低（P<0.01）；而miR-887-3p过表达组中Bcl-2和MDM4表达水平显著降低（P<0.05），Caspase-3的表达水平显著升高（P<0.05）。实时荧光定量PCR和蛋白免疫印迹结果显示，干扰miR-887-3p后，MDM4蛋白和mRNA的表达增加（P<0.001）；过表达miR-887-3p后，MDM4蛋白和mRNA的表达降低（P<0.01，P<0.001）。结论 miR-887-3p可能通过调控MDM4的表达来影响大鼠椎间盘纤维环细胞的增殖和凋亡，进而影响椎间盘退变的发生和发展。

关键词: 微RNA-887-3p, 椎间盘纤维环细胞, 退变模型, 细胞增殖, 细胞凋亡, 大鼠

Abstract:

Objective To investigate the effects of microRNA (miRNA, miR)-887-3p on the proliferation and apoptosis of rat intervertebral disc annulus fibrosus cells and its underlying molecular mechanism. Methods Annulus fibrosus tissues were obtained from 8-week-old SPF-grade SD male rats, centrifuged to prepare and identify annulus fibrosus cells. Rats in the experiment were randomly divided into four groups: a Normal group consisting of primary annulus fibrosus cells without any treatment; a Control group treated with 10 ng/mL interleukin-1β (IL-1β) for 24 hours to establish a degenerative cell model; an interference group (miR-887-3p inhibitor) transfected with miR-887-3p inhibitor using Lipo3000 based on the Control group; and an overexpression group (miR-887-3p mimics) transfected with miR-887-3p mimics using Lipo3000 based on the Control group. CCK-8 assay was used to assess cell viability; flow cytometry was used to measure cell apoptosis rates; real-time fluorescence quantitative PCR (qPCR) was used to detect the expression levels of miR-887-3p and murine double minute 4 (MDM4) mRNA; Western blotting was used to measure the protein expression levels of MDM4, Bcl-2, and Caspase-3. Results Immunofluorescence staining of isolated and cultured cells revealed a Collagen I positive rate of over 90% in rat intervertebral disc annulus fibrosus cells, indicating a cell purity level greater than 90%. Real-time fluorescence qPCR results showed that after establishing an annulus fibrosus degenerative cell model using IL-1β, the expression level of miR-887-3p significantly increased compared to the Normal group (P<0.001). Compared to the Control group, transfection with miR-887-3p inhibitor resulted in a significant decrease in its expression level (P<0.001). The CCK-8 assay showed that compared to the Normal group, cell viability significantly decreased in the Control group (P<0.001). Compared to the Control group, cell proliferation ability significantly increased after miR-887-3p inhibition, and significantly decreased after overexpression of miR-887-3p. Flow cytometry results revealed that compared to the Normal group, the apoptosis rate in the Control group significantly increased (P<0.001). Compared to the Control group, the cell apoptosis rate significantly decreased in the miR-887-3p interference group (P<0.001) and increased in the overexpression group (P<0.001). Western blotting analysis showed that compared to the Normal group, Bcl-2 expression level significantly decreased (P<0.001) and Caspase-3 expression level significantly increased (P<0.001) in the Control group. Compared to the Control group, Bcl-2 and MDM4 expression levels significantly increased (P<0.01), and Caspase-3 expression level significantly decreased (P<0.01) in the miR-887-3p interference group; whereas in the overexpression group, Bcl?2 and MDM4 expression levels significantly decreased (P<0.05), and Caspase-3 levels significantly increased (P<0.05). Real-time fluorescence qPCR and protein immunoblotting results showed that after interfering with miR-887-3p, the expression of MDM4 protein and mRNA increased (P<0.001); after overexpressing miR-887-3p, their expression decreased (protein, P<0.01; mRNA, P<0.001). Conclusion MiR-887-3p may modulate the cell proliferation and apoptosis of rat intervertebral disc annulus fibrosus cells by regulating MDM4 expression, thereby influencing the development and progression of disc degeneration.

Key words: miR-887-3p, Intervertebral disc annulus fibrosus cells, Degenerative model, Cell proliferation, Apoptosis, Rats

中图分类号:

R681.5

朱晓雨,袁韩涛,李四波. 微RNA-887-3p能抑制大鼠椎间盘纤维环细胞中 MDM4表达和细胞增殖并促进细胞凋亡[J]. 实验动物与比较医学, 2024, 44(3): 270-278. DOI: 10.12300/j.issn.1674-5817.2024.003.

Xiaoyu ZHU,Hantao YUAN,Sibo LI. MicroRNA-887-3p Inhibited MDM4 Expression and Proliferation but Promoted Apoptosis of Intervertebral Disc Annulus Fibrosus Cells in Rats[J]. Laboratory Animal and Comparative Medicine, 2024, 44(3): 270-278. DOI: 10.12300/j.issn.1674-5817.2024.003.

图/表 5

图1 大鼠椎间盘纤维环细胞鉴定及miR-887-3p表达水平检测注：A，免疫荧光染色法鉴定大鼠椎间盘纤维环细胞（Collagen I表达被Cy3荧光抗体标记后显红色；DAPI染色细胞核呈蓝色；Merged为两者叠加；比例尺：100 μm）。B，实时荧光定量PCR检测miR-887-3p抑制子和模拟物转染后的miR-887-3p相对表达量（与正常组相比，***P<0.001；与对照组相比，###P<0.001）。

Figure 1 Identification of rat intervertebral disc annulus fibrosus cells and detection of miR-887-3p expression levelsNote： A, Immunofluorescence staining was used to identify rat intervertebral disc annulus fibrosus cells (Collagen I expression marked by Cy3 fluorescent antibody appeared red; cell nuclei stained with DAPI appeared blue; Merged, the overlay of A and B; Scale bar: 100 μm). B, Relative expression of miR-887-3p after transfection with miR-887-3p inhibitor and mimics detected by real-time fluorescence quantitative PCR. Compared to the normal group, ***P<0.001; Compared to the control group, ###P<0.001.

表1 CCK-8检测miR-887-3p抑制子和模拟物转染后大鼠椎间盘纤维环细胞的增殖能力

Table 1 CCK-8 assay used to test cell proliferation ability of rat intervertebral disc annulus fibrosus cells after transfection with miR-887-3p inhibitor and mimics

组别 Groups	细胞活力 /% Cell viability /%
组别 Groups	12 h	24 h	48 h	72 h
正常组（Normal group）	100.00±3.24	100.00±2.65	100.0±3.02	100.00±1.24
对照组（Control group）	98.65±2.54	75.25±6.26^**	62.40±6.86^***	36.54±2.04^***
miR-887-3p inhibitor	96.56±2.23	95.46±1.25	94.54±3.01	95.23±2.25
miR-887-3p mimics	95.71±1.62	62.71±7.62^**##	40.74±5.13^***###	23.15±3.63^***###

图2 流式细胞仪检测转染miR-887-3p抑制子和模拟物转染后48 h的大鼠椎间盘纤维环细胞凋亡率注：与正常组相比，***P<0.001；与对照组相比，###P<0.001。

Figure 2 Flow cytometry measurement of apoptosis rates in rat intervertebral disc annulus fibrosus cells 48 h after transfection with miR-887-3p inhibitor and mimicsNote： Compared to the normal group， ***P<0.001； Compared to the control group， ###P<0.001.

图3 蛋白质印迹法检测瞬时转染miR-887-3p抑制子和模拟物48 h后大鼠椎间盘纤维环细胞中Bcl-2（A）和Caspase-3（B）蛋白表达注：与正常组相比，***P<0.001；与对照组相比，#P<0.05，##P<0.01。

Figure 3 Western blotting analysis of Bcl-2（A） and Caspase-3（B） protein expression in rat intervertebral disc annulus fibrosus cells 48 h after transient transfection with miR-887-3p inhibitor and mimicsNote： Compared to the normal group， ***P<0.001； Compared to the control group， #P<0.05， ##P<0.01.

图4 瞬时转染miR-887-3p抑制子和模拟物48 h后大鼠椎间盘纤维环细胞中MDM4 mRNA和蛋白表达的变化注：蛋白质印迹法（A）和实时荧光定量PCR（B）检测鼠双微体4（MDM4）的表达。与正常组相比，**P<0.01，***P<0.001；与对照组相比，##P<0.01，###P<0.001。

Figure 4 Changes in MDM4 mRNA and protein expression in rat intervertebral disc annulus fibrosus cells 48 h after transient transfection with miR-887-3p inhibitor and mimicsNote： Expression of murine double minute 4 (MDM4) was detected by Western blotting (A) and real-time fluorescence quantitative PCR (B). Compared to the normal group, **P<0.01, ***P<0.001; Compared to the control group, ###P<0.001.

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微RNA-887-3p能抑制大鼠椎间盘纤维环细胞中 MDM4表达和细胞增殖并促进细胞凋亡

MicroRNA-887-3p Inhibited MDM4 Expression and Proliferation but Promoted Apoptosis of Intervertebral Disc Annulus Fibrosus Cells in Rats

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