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中华细胞与干细胞杂志(电子版)

中华细胞与干细胞杂志(电子版) ›› 2023, Vol. 13 ›› Issue (03) : 129 -136. doi: 10.3877/cma.j.issn.2095-1221.2023.03.001

论著

LncRNA CRNDE通过miR-181a-5p/SOX6轴调节脂多糖诱导人肺泡上皮细胞的炎症反应和细胞凋亡
邓春文, 陈嵩†(), 钟裴, 闵师强, 万健   
  1. 201299，上海市浦东新区人民医院急诊与重症医学科
  • 收稿日期:2023-01-16 出版日期:2023-06-01
  • 通信作者: 陈嵩
  • 基金资助:
    浦东新区科技发展基金民生科研专项(PKJ2020-Y43)

LncRNA CRNDE regulates lipopolysaccharide-induced inflammatory response and apoptosis in human alveolar epithelial cells via miR-181a-5p/SOX6 axis

Chunwen Deng, Song Chen†(), Pei Zhong, Shiqiang Min, Jian Wan   

  1. Department of Emergency and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai 201299, China
  • Received:2023-01-16 Published:2023-06-01
  • Corresponding author: Song Chen
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引用本文：

邓春文, 陈嵩, 钟裴, 闵师强, 万健. LncRNA CRNDE通过miR-181a-5p/SOX6轴调节脂多糖诱导人肺泡上皮细胞的炎症反应和细胞凋亡[J]. 中华细胞与干细胞杂志(电子版), 2023, 13(03): 129-136.

Chunwen Deng, Song Chen, Pei Zhong, Shiqiang Min, Jian Wan. LncRNA CRNDE regulates lipopolysaccharide-induced inflammatory response and apoptosis in human alveolar epithelial cells via miR-181a-5p/SOX6 axis[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(03): 129-136.

目的

探索长链非编码RNA （LncRNA）CRNDE通过微小RNA-181a-5p （miR-181a-5p）/转录因子性别决定区Y-box 6 （SOX6）轴对脂多糖（LPS）诱导人肺泡上皮细胞炎症反应和细胞凋亡的影响。

方法

将所有质粒和寡核苷酸分别转染A549细胞，并进行LPS处理，并以未经处理的A549细胞为对照。qRT-PCR检测细胞中CRNDE、miR-181a-5p以及SOX6 mRNA的表达水平；流式细胞仪、ELISA法检测细胞凋亡及肿瘤坏死因子-α （TNF-α）、炎症因子白细胞介素-1β （IL-β）和IL-6水平；双荧光素酶实验分别验证CRNDE和miR-181a-5p以及miR-181a-5p与SOX6的靶向关系；Western blot检测磷酸化（p）-核因子κB （NF-κB） p65/NF-κB p65、SOX6、活化的半胱氨酸天冬氨酸酶3 （cleaved caspase-3）的表达水平。两组间比较采用独立样本t检验；各组数据均满足正态分布，当方差齐时采用单因素方差分析，进一步两组间比较采用SNK-q检验，方差不齐时采用Games-Howell法检验。

结果

与对照比较，LPS的细胞凋亡率[（41.11 ± 4.11）%比（6.11 ± 0.61）%]、TNF-α [（353.21 ± 35.31）比（200.15 ± 20.02）pg/mg]、IL-1β [（286.91 ± 28.71）比（35.76 ± 3.58）pg/mg]、IL-6[（642.31 ± 64.23）比（32.64 ± 3.26）pg/mg]、CRNDE （0.66 ± 0.06比0.33 ± 0.03）、SOX6 （0.68 ± 0.06比0.28 ± 0.03）、cleaved caspase-3 （0.76 ± 0.07比0.24 ± 0.02）、p-NF-κB p65/NF-κB p65 （0.85 ± 0.08比0.26 ± 0.03）升高，miR-181a-5p表达（0.32 ± 0.03比0.64 ± 0.06）降低（P < 0.05）；与si-NC组相比，干扰CRNDE降低LPS诱导细胞的凋亡率[（15.58 ± 1.55）%比（41.09 ± 4.09）%]、TNF-α[（200.15 ± 20.02）比（356.51 ± 35.65）pg/mg]、IL-1β[（99.32 ± 9.94）比（288.88 ± 28.89 ） pg/mg]、IL-6[（211.34 ± 21.14）比（639.89 ± 63.99）pg/mg]、CRNDE（0.35 ± 0.03比0.65 ± 0.06）、SOX6 （0.39 ± 0.04比0.64 ± 0.07）的表达（P < 0.05），干扰SOX6降低LPS诱导细胞的凋亡率[（15.34 ± 1.53）%比（41.09 ± 4.09）%]、TNF-α[（192.37 ± 19.24）比（356.51 ± 35.65）pg/mg]、IL-1β [（100.02 ± 10.01）比（288.88 ± 28.89）pg/mg]、IL-6[（204.86 ± 20.49）比（639.89 ± 63.99）pg/mg]、SOX6 （0.36 ± 0.03比0.64 ± 0.07）的表达（P < 0.05）；与miR-NC相比，过表达miR-181a-5p降低LPS诱导细胞的凋亡率[（15.34 ± 1.53）%比（40.89 ± 4.09）%]、TNF-α [（189.45 ± 19.01）比（356.68 ± 35.67）pg/mg]、IL-1β[（95.37 ± 9.54）比（288.67 ± 28.87） pg/mg]、IL-6[（209.84 ± 20.98）比（637.93 ± 63.81）pg/mg]水平，miR-181a-5p （0.55 ± 0.05比0.35 ± 0.03）表达增加（P < 0.05）。抑制miR-181a-5p表达可逆转干扰CRNDE对LPS诱导A549细胞的保护作用；上调SOX6可逆转干扰CRNDE、过表达miR-181a-5p对LPS诱导A549细胞的保护作用。

结论

干扰CRNDE可以抑制LPS诱导A549细胞的炎症反应和细胞凋亡，可能与调控miR-181a-5p/SOX6轴有关。

关键词: LncRNA CRNDE, miR-181a-5p/SOX6轴, LPS, 炎症反应, 细胞凋亡
Objective

To explore the effects of long non-coding RNA (lncRNAs) CRNDE on lipopolysaccharide (LPS) -induced inflammatory response and apoptosis of human alveolar epithelial cells via the microRNA-181a-5p (miR-181a-5p) /transcription factor sex-determining region Y-box 6 (SOX6) axis.

Methods

All plasmids and oligonucleotides were transfected into A549 cells and treated with LPS. Untreated A549 cells were used as the control. QRT-PCR was performed to detect the expression levels of CRNDE, miR-181a-5p and SOX6 mRNA in cells; flow cytometry and ELISA were performed to detect cell apoptosis and the levels of tumor necrosis factor-α (TNF-α) , inflammatory factors interleukin-1β (IL-1β) and IL-6; dual luciferase experiment was performed to verify the targeting relationship between CRNDE and miR-181a-5p, and the relationship between miR-181a-5p and SOX6; Western blot was performed to detect the expression levels of phosphorylated (p) -nuclear factor κB (NF-κB) p65/NF-κB p65, SOX6 and cleaved caspase-3.

Results

Compared with the control, the apoptosis rate (41.11%± 4.11%) vs (6.11% ± 0.61%) , TNF-α (353.21 ± 35.31) vs (200.15 ± 20.02) pg/mg, IL-1β (286.91 ± 28.71) vs (35.76 ± 3.58) pg/mg, IL-6 (642.31 ± 64.23 vs 32.64 ± 3.26) pg/mg, the expression of CRNDE (0.66 ± 0.06 vs 0.33 ± 0.03) , SOX6 (0.68 ± 0.06 vs 0.28 ± 0.03) , cleaved caspase-3 (0.76 ± 0.07 vs 0.24 ± 0.02) , p-NF-κB p65/NF-κB p65 (0.85 ± 0.08 vs 0.26 ± 0.03) were visibly raised in the LPS group, and the expression of miR-181a-5p (0.32 ± 0.03 vs 0.64 ± 0.06) was visibly decreased (P < 0.05) ; Compared with the si-NC group, knockdown CRNDE decreased the apoptosis rate (15.58%± 1.55% vs 41.09%± 4.09%) , TNF-α[ (200.15 ± 20.02) vs (356.51 ± 35.65) pg/mg], IL-1β[ (99.32 ± 9.94) vs (288.88 ± 28.89) pg/mg], IL-6[ (211.34 ± 21.14) vs (639.89 ± 63.99) pg/mg], CRNDE (0.35 ± 0.03 vs 0.65 ± 0.06) , SOX6 (0.39 ± 0.04 vs 0.64 ± 0.07) induced by LPS (P < 0.05) , Knockdown SOX6 inhibited the apoptosis rate (15.34%± 1.53% vs 41.09%± 4.09%) , TNF-α[ (192.37 ± 19.24) vs (356.51 ± 35.65) pg/mg], IL-1β[ (100.02 ± 10.01) vs (288.88 ± 28.89) pg/mg]. The expression of IL-6[(204.86 ± 20.49) vs (639.89 ± 63.99) pg/mg], SOX6 (0.36 ± 0.03 vs 0.64 ± 0.07) induced by LPS (P < 0.05) ; Compared with miR-NC, overexpression of miR-181a-5p reduced apoptosis (15.34%± 1.53% vs 40.89%± 4.09%) , TNF-α[ (189.45 ± 19.01) vs (356.68 ± 35.67) pg/mg], IL-1β[ (95.37 ± 9.54) vs (288.67 ± 28.8 7) pg/mg], IL-6[ (209.84 ± 20.98) vs (637.93 ± 63.81) pg/mg]induced by LPS, and the expression of miR-181a-5p (0.55 ± 0.05 vs 0.35 ± 0.03) was significantly increased (P < 0.05) ; inhibiting the expression of miR-181a-5p could reverse the protective effect of CRNDE on LPS-induced A549 cells; up-regulation of SOX6 could reverse the protective effects of CRNDE interference and miR-181a-5p overexpression on LPS-induced A549 cells.

Conclusion

Interfering with CRNDE could inhibit the inflammatory response and apoptosis of A549 cells induced by LPS, which may be related to the regulation of the miR-181a-5p/SOX6 axis.

Key words: LncRNA CRNDE, miR-181a-5p/SOX6 axis, LPS, Inflammatory response, Apoptosis
表1 qRT-PCR引物序列信息
基因 序列（5'→3'） 预期扩增引物长度（bp）
CRNDE 上游TGAAGGAAGGAAGTGGTGCA 186
  下游TCCAGTGGCATCCTACAAGA  
miR-181a-5p 上游AACAUUCAACGCUGUCGGUGAGU 246
  下游UUUUGUAAGUUGCGACAGCCACU  
SOX6 上游CCCCTCTGAACATGGTGGTGGC 113
  下游TGAGACTGCCCCTGCCGAGT  
β-actin 上游AGAAAATCTGGCACCACACC 153
  下游CCATCTCTTGCTCGAAGTCC  
U6 上游CTCGCTTCGGCAGCACA 105
  下游AACGCTTCACGAATTTGCGT  
表2 比较CRNDE、miR-181a-5p以及SOX6 mRNA表达（ ± s）
分组 实验次数 CRNDE miR-181a-5p SOX6 mRNA
对照 6 0.33 ± 0.03 0.64 ± 0.06 0.28 ± 0.03
LPS 6 0.66 ± 0.06 0.32 ± 0.03 0.68 ± 0.06
t值   12.050 11.685 14.606
P值   < 0.001 < 0.001 < 0.001
图1 流式细胞术检测细胞凋亡注：a ~ g图分别为对照、LPS、LPS+si-NC、LPS+si-CRNDE、LPS+si-SOX6、miR-NC、LPS+miR-181a-5p
表3 分别干扰CRNDE、SOX6对LPS诱导的细胞凋亡、炎症因子以及CRNDE表达的影响（ ± s）
分组 实验次数 CRNDE SOX6 mRNA 凋亡率（%） TNF-α （pg/mg） IL-1β （pg/mg） IL-6 （pg/mg）
对照 6 0.33 ± 0.03 0.28 ± 0.03 6.11 ± 0.61 88.45 ± 8.85 35.76 ± 3.58 32.64 ± 3.26
LPS 6 0.66 ± 0.06a 0.68 ± 0.06a 41.11 ± 4.11a 353.21 ± 35.31a 286.91 ± 28.71a 642.31 ± 64.23a
LPS+si-NC 6 0.65 ± 0.06a 0.64 ± 0.07a 41.09 ± 4.09a 356.51 ± 35.65a 288.88 ± 28.89a 639.89 ± 63.99a
LPS+si-CRNDE 6 0.35 ± 0.03bc 0.39 ± 0.04abc 15.58 ± 1.55abc 200.15 ± 20.02abc 99.32 ± 9.94abc 211.34 ± 21.14abc
LPS+si-SOX6 6 0.33 ± 0.03bc 0.36 ± 0.03abc 15.34 ± 1.53abc 192.37 ± 19.24abc 100.02 ± 10.01abc 204.86 ± 20.49abc
F值   92.363 80.420 203.425 118.497 222.138 255.907
P值   < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
表4 上调miR-181a-5p对细胞凋亡、炎症因子以及miR-181a-5p表达的影响（ ± s）
分组 实验次数 miR-181a-5p 凋亡率（%） TNF-α （pg/mg） IL-1β （pg/mg） IL-6 （pg/mg）
LPS 6 0.32 ± 0.03 41.02 ± 4.09 358.43 ± 35.84 288.14 ± 28.81 642.67 ± 64.31
miR-NC 6 0.35 ± 0.03 40.89 ± 4.09 356.68 ± 35.67 288.67 ± 28.87 637.93 ± 63.81
miR-181a-5p 6 0.55 ± 0.05ab 15.34 ± 1.53ab 189.45 ± 19.01ab 95.37 ± 9.54ab 209.84 ± 20.98ab
F值   65.442 109.977 58.107 127.430 128.575
P值   < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
图2 Western blot检测各组细胞p-NF-κB p65、NF-κB p65、SOX6、cleaved caspase-3蛋白表达注：1为对照；2为LPS；3为LPS+si-NC；4为LPS+si-CRNDE；5为LPS+si-SOX6；6为LPS+miR-NC；7为LPS+miR-181a-5p
表5 分别干扰CRNDE、SOX6或上调miR-181a-5p对相关蛋白表达的影响（ ± s）
分组 实验次数 SOX6/β-actin p-NF-κB p65/NF-κB p65 cleaved caspase-3/β-actin
对照 6 0.31 ± 0.03 0.26 ± 0.03 0.24 ± 0.02
LPS 6 0.67 ± 0.06a 0.85 ± 0.08a 0.76 ± 0.07a
LPS+si-NC 6 0.66 ± 0.06a 0.82 ± 0.08a 0.78 ± 0.08a
LPS+miR-NC 6 0.65 ± 0.06a 0.84 ± 0.08a 0.80 ± 0.08a
LPS+si-CRNDE 6 0.35 ± 0.03bcd 0.34 ± 0.03bcd 0.29 ± 0.03bcd
LPS+si-SOX6 6 0.32 ± 0.03bcd 0.32 ± 0.03bcd 0.34 ± 0.03bcd
LPS+miR-181a-5p 6 0.29 ± 0.03bcd 0.35 ± 0.03bcd 0.32 ± 0.03bcd
F值   98.760 143.500 127.300
P值   < 0.001 < 0.001 < 0.001
图3 Western blot检测各组细胞p-NF-κB p65、NF-κB p65、SOX6和cleaved caspase-3蛋白表达注：1为LPS+si-CRNDE+anti-miR-NC；2为LPS+si-CRNDE+anti-miR-181a-5p；3为LPS+si-CRNDE+oe-NC；4为LPS+si-CRNDE+oe-SOX6；5为LPS+miR-181a-5p+oe-NC；6为LPS+miR-181a-5p+oe-SOX6
图4 流式细胞术检测细胞凋亡注：a ~ f图分别为LPS+si-CRNDE+anti-miR-NC、LPS+si-CRNDE+anti-miR-181a-5p、LPS+si-CRNDE+oe-NC、LPS+si-CRNDE+oe-SOX6、LPS+miR-181a-5p+oe-NC、LPS+miR-181a-5p+oe-SOX6
表6 抑制miR-181a-5p可逆转干扰CRNDE对LPS诱导A549细胞凋亡、炎症因子的影响（ ± s）
分组 实验次数 细胞凋亡率（%） TNF-α （pg/mg） IL-1β （pg/mg） IL-6 （pg/mg）
LPS+si-CRNDE+anti-miR-NC 6 40.01 ± 4.01 333.21 ± 33.31 256.45 ± 25.64 634.32 ± 63.43
LPS+si-CRNDE+anti-miR-181a-5p 6 55.24 ± 5.52 456.32 ± 45.63 376.42 ± 37.65 868.31 ± 86.82
t值   5.468 5.338 6.451 5.331
P值   < 0.001 < 0.001 < 0.001 < 0.001
分组 实验次数 SOX6/β-actin p-NF-κB p65/NF-κB p65 cleaved caspase-3/β-actin
LPS+si-CRNDE+anti-miR-NC 6 0.65 ± 0.06 0.83 ± 0.08 0.75 ± 0.07
LPS+si-CRNDE+anti-miR-181a-5p 6 0.94 ± 0.09 1.08 ± 0.10 0.96 ± 0.09
t值   6.567 4.782 4.512
P值   < 0.001 0.001 0.001
表7 过表达SOX6可逆转干扰CRNDE对LPS诱导A549细胞凋亡、炎症因子的影响（ ± s）
分组 实验次数 细胞凋亡率（%） TNF-α （pg/mg） IL-1β （pg/mg） IL-6 （pg/mg） SOX6/β-actin
LPS+si-CRNDE+oe-NC 6 39.84 ± 3.99 346.38 ± 34.64 235.71 ± 23.57 621.28 ± 62.13 0.66 ± 0.06
LPS+si-CRNDE+oe-SOX6 6 50.19 ± 5.02 462.31 ± 46.23 378.52 ± 37.85 871.64 ± 87.17 0.89 ± 0.09
t值   3.954 4.916 7.845 5.729 5.208
P值   0.003 0.001 < 0.001 < 0.001 < 0.001
分组 实验次数 p-NF-κB p65/NF-κB p65 cleaved-caspase-3/β-actin SOX6 mRNA CRNDE
LPS+si-CRNDE+oe-NC 6 0.82 ± 0.08 0.72 ± 0.07 0.39 ± 0.03 0.35 ± 0.04
LPS+si-CRNDE+oe-SOX6 6 1.11 ± 0.11 0.98 ± 0.09 0.56 ± 0.06 0.36 ± 0.03
t值   5.223 5.586 6.208 0.490
P值   < 0.001 < 0.001 < 0.001 0.6351
表8 上调SOX6可逆转过表达miR-181a-5p对细胞凋亡、炎症因子的影响（ ± s）
分组 实验次数 细胞凋亡率（%） TNF-α （pg/mg） IL-1β （pg/mg） IL-6 （pg/mg）
LPS+miR-181a-5p+oe-NC 6 40.18 ± 4.02 349.51 ± 34.96 248.72 ± 24.87 618.91 ± 61.91
LPS+miR-181a-5p+oe-SOX6 6 52.43 ± 5.24 467.43 ± 46.74 369.89 ± 36.99 875.34 ± 87.53
t值   7.462 4.949 6.659 8.710
P值   < 0.001 0.001 < 0.001 < 0.001
分组 实验次数 SOX6/β-actin p-NF-κB p65/NF-κB p65 cleaved caspase-3/β-actin
LPS+miR-181a-5p+oe-NC 6 0.63 ± 0.06 0.84 ± 0.08 0.73 ± 0.07
LPS+miR-181a-5p+oe-SOX6 6 0.92 ± 0.09 1.09 ± 0.10 0.97 ± 0.09
t值   6.567 4.782 5.156
P值   < 0.001 0.001 < 0.001
图5 LncBase Predicted v.2预测CRNDE与miR-181a-5p的关系
表9 LncBase Predicted v.2预测及靶向验证CRNDE与miR-181a-5p的关系
因素 实验次数 WT-CRNDE MUT-CRNDE
miR-NC 6 1.11 ± 0.11 1.06 ± 0.11
miR-181a-5p 6 0.42 ± 0.03 1.09 ± 0.11
t值   14.609 0.472
P值   < 0.001 0.647
图6 Targetscan预测SOX6与miR-181a-5p的结合位点
表10 验证SOX6与miR-181a-5p的靶向关系（ ± s）
因素 实验次数 WT-SOX6 MUT-SOX6
miR-NC 6 1.12 ± 0.11 1.08 ± 0.11
miR-181a-5p 6 0.44 ± 0.03 1.13 ± 0.11
t值   14.609 0.787
P值   < 0.001 0.449
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