CircCDR1as调节miR-671-5p/CBX4轴对NSCLC细胞生物学行为的影响

doi:10.11958/20221405

天津医药 ›› 2023, Vol. 51 ›› Issue (6): 573-579.doi: 10.11958/20221405

CircCDR1as调节miR-671-5p/CBX4轴对NSCLC细胞生物学行为的影响

杜文峰(), 周玲, 李琪()

武汉科技大学附属普仁医院呼吸与危重症科（邮编430081）

收稿日期:2022-09-02 修回日期:2022-10-21 出版日期:2023-06-15 发布日期:2023-06-20
通讯作者: ^△E-mail：optimum1212@163.com
作者简介:杜文峰（1987），男，主治医师，主要从事肺癌、慢性阻塞性肺疾病及哮喘方面研究。E-mail：duzvyn@163.com
基金资助:
2020年度中国金属学会冶金安全与健康分会健康卫生科研项目(jkws202005)

Effects of CircCDR1as on the biological behavior of NSCLC cells by regulating the miR-671-5p/CBX4 axis

DU Wenfeng(), ZHOU Ling, LI Qi()

Department of Respiratory and Critical Care, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan 430081, China

Received:2022-09-02 Revised:2022-10-21 Published:2023-06-15 Online:2023-06-20
Contact: ^△E-mail：optimum1212@163.com

杜文峰, 周玲, 李琪. CircCDR1as调节miR-671-5p/CBX4轴对NSCLC细胞生物学行为的影响[J]. 天津医药, 2023, 51(6): 573-579.

DU Wenfeng, ZHOU Ling, LI Qi. Effects of CircCDR1as on the biological behavior of NSCLC cells by regulating the miR-671-5p/CBX4 axis[J]. Tianjin Medical Journal, 2023, 51(6): 573-579.

摘要/Abstract

摘要：

目的探讨环状RNA（CircRNA）反义小脑变性相关蛋白1转录本（CircCDR1as）通过调节miR-671-5p/染色盒同源物4（CBX4）轴对非小细胞肺癌（NSCLC）细胞增殖、凋亡、迁移和侵袭的影响。方法体外培养人NSCLC细胞株（NCI-H524、NCI-H1734、Calu-3和A549）和人支气管上皮样细胞（HBE）。A549细胞分成Control组、si-NC组、si-CircCDR1as组、si-CircCDR1as+anti-miR-NC组、si-CircCDR1as+anti-miR-671-5p组、pcDNA组、CircCDR1as组、miR-NC组、miR-671-5p组、miR-671-5p+pcDNA组、miR-671-5p+CBX4组、anti-miR-NC组和anti-miR-671-5p组。采用实时定量聚合酶链反应（qRT-PCR）检测CircCDR1as、miR-671-5p和CBX4 mRNA表达。Western blot检测CBX4蛋白表达。分别采用四甲基偶氮唑盐（MTT）、克隆形成实验、流式细胞术和Transwell检测细胞活力、增殖、凋亡、迁移和侵袭。通过双荧光素酶报告基因检测验证miR-671-5p与CircCDR1as或CBX4之间的靶向关系。结果与HBE细胞相比，CircCDR1as和CBX4在4种NSCLC细胞中表达升高，miR-671-5p表达降低（P<0.05）。与si-NC组比较，si-CircCDR1as组A549细胞活力和克隆形成数显著降低，细胞迁移和侵袭数目减少，凋亡率增高（P<0.05）。miR-671-5p作为CircCDR1as的靶点，其下调减弱了CircCDR1as沉默对NSCLC进展的调控作用（P<0.05）。miR-671-5p靶向CBX4在体外抑制NSCLC的恶性进展（P<0.05）。沉默CircCDR1as可通过上调miR-671-5p水平降低CBX4的表达（P<0.05）。结论 CircCDR1as沉默可通过上调miR-671-5p和下调CBX4表达来抑制细胞增殖、迁移和侵袭，诱导细胞凋亡。

关键词: 癌, 非小细胞肺, A549细胞, CircRNA反义小脑变性相关蛋白1转录本, miR-671-5p, 染色盒同源物4

Abstract:

Objective To investigate effects of CircRNA antisense cerebellar degeneration-related protein 1 transcript (CircCDR1as) on the proliferation, apoptosis, migration and invasion of non-small cell lung cancer (NSCLC) cells by regulating miR-671-5p/chromobox 4 (CBX4) axis. Methods Human NSCLC cell lines (NCI-H524, NCI-H1734, Calu-3 and A549) and human bronchial epithelioid cells (HBE) were cultured in vitro. A549 cells were randomly separated into the control group, the si-NC group, the si-CircCDR1as group, the si-CircCDR1as+anti-miR-NC group, the si-CircCDR1as+anti-miR-671-5p group, the pcDNA group, the CircCDR1as group, the miR-NC group, the miR-671-5p group, the miR-671-5p+pcDNA group, the miR-671-5p+CBX4 group, the anti-miR-NC group and the anti-miR-671-5p group. The expression levels of CircCDR1as, miR-671-5p and CBX4 mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of CBX4 was detected by Western blot assay. The cell viability, proliferation, apoptosis, migration and invasion were detected by tetramethylazolium salt (MTT), clonogenic assay, flow cytometry and Transwell, respectively. The targeting relationship between miR-671-5p and CircCDR1as or CBX4 was verified by dual-luciferase reporter assay. Results Compared with HBE cells, expression levels of CircCDR1as and CBX4 were increased and the expression of miR-671-5p was decreased in the four NSCLC cell groups (P<0.05). Compared with the si-NC group, the viability and the number of colonies of A549 cells were obviously decreased in the si-CircCDR1as group, the numbers of cell migration and invasion were decreased, and the apoptosis rate was increased (P<0.05). The down regulation of miR-671-5p, a target of CircCDR1as, attenuated the regulatory effect of CircCDR1as silencing on NSCLC progression (P<0.05). miR-671-5p targeting CBX4 inhibited the malignant progression of NSCLC in vitro (P<0.05). The down regulation of CircCDR1as could reduce the expression of CBX4 by up-regulating the level of miR-671-5p (P<0.05). Conclusion CircCDR1as silencing can inhibit cell proliferation, migration and invasion and induce cell apoptosis by up-regulating miR-671-5p and down-regulating CBX4.

Key words: carcinoma, non-small-cell lung, A549 cells, CircRNA antisense cerebellar degeneration-related protein 1 transcript, miR-671-5p, chromobox 4

中图分类号:

R734.2

图/表 13

图1 HBE细胞和NSCLC细胞系中CBX4蛋白的表达

Fig.1 CBX4 protein expression in HBE cells and NSCLC cell lines

表1 HBE细胞和NSCLC细胞系中CircCDR1as、miR-671-5p、CBX4表达水平（n=6，$\bar{x}±s$）

Tab.1 CircCDR1as, miR-671-5p and CBX4 levels in HBE cells and NSCLC cell lines

细胞系	CircCDR1as	miR-671-5p	CBX4 mRNA	CBX4蛋白
HBE	1.00±0.01	1.00±0.02	1.00±0.02	1.00±0.03
NCI-H524	3.92±0.14^a	0.59±0.05^a	2.86±0.14^a	2.54±0.11^a
NCI-H1734	4.09±0.21^a	0.52±0.06^a	2.95±0.18^a	2.63±0.14^a
Calu-3	4.15±0.19^a	0.41±0.04^a	3.18±0.23^a	2.75±0.21^a
A549	4.29±0.28^a	0.32±0.02^a	3.32±0.25^a	2.89±0.16^a
F	328.965^＊＊	243.424^＊＊	160.266^＊＊	175.065^＊＊

图2 通过starBase预测CircCDR1as和miR-671-5p的结合位点

Fig.2 The binding sites of CircCDR1as and miR-671-5p predicted by starBase

图3 各组NSCLC细胞凋亡、迁移和侵袭情况（结晶紫染色，×200）

Fig.3 Apoptosis, migration and invasion of NSCLC cells in each group (crystal violet staining, ×200)

表2 各组NSCLC细胞活力、克隆形成数、凋亡率、迁移侵袭细胞数比较（n=6，$\bar{x}±s$）

Tab.2 Comparison of NSCLC cell viability, number of clone formation, apoptosis rate, migration and number of invasive cells between the five groups

组别	CircCDR1as	miR-671-5p	细胞活力（OD₄₉₀值）	克隆形成数（个）	凋亡率（%）	迁移细胞数（个）	侵袭细胞数（个）
Control组	1.00±0.03	1.00±0.02	1.18±0.21	91.45±7.62	10.02±0.91	94.38±8.12	97.56±6.89
si-NC组	1.00±0.02	0.99±0.03	1.17±0.19	91.38±7.49	10.01±0.89	94.29±7.91	97.54±6.85
si-CircCDR1as组	0.38±0.03^ab	1.78±0.06^ab	0.49±0.07^ab	38.62±3.51^ab	33.45±2.62^ab	40.15±10.03^ab	41.32±8.74^ab
si-CircCDR1as+anti-miR-NC组	0.39±0.02	1.75±0.08	0.47±0.06	38.67±3.48	33.48±2.14	40.18±10.06	41.35±6.95
si-CircCDR1as+anti-miR-671-5p组	0.91±0.05^cd	1.26±0.05^cd	0.99±0.12^cd	80.59±6.72^cd	14.13±1.06^cd	79.84±9.21^cd	80.69±7.24^cd
F	611.941^＊＊	328.761^＊＊	36.693^＊＊	121.564^＊＊	315.182^＊＊	55.305^＊＊	90.091^＊＊

图4 StarBase预测miR-671-5p和CBX4的结合位点

Fig.4 The binding sites of miR-671-5p and CBX4 predicted by StarBase

图5 各组A549细胞中CBX4蛋白表达 A：miR-NC组；B：miR-671-5p组；C：anti-miR-NC组；D：anti-miR-671-5p组。

Fig.5 CBX4 protein expression in A549 cells of each group

表3 各组A549细胞中CBX4的mRNA和蛋白水平比较（n=6，$\bar{x}±s$）

Tab.3 Comparison of mRNA and protein levels of CBX4 in A549 cells between the four groups

组别	CBX4 mRNA	CBX4蛋白
miR-NC组	1.00±0.01	1.00±0.03
miR-671-5p组	0.38±0.04^a	0.42±0.04^a
anti-miR-NC组	1.00±0.02	1.00±0.02
anti-miR-671-5p组	2.12±0.06^b	1.71±0.08^b
F	2 212.351^＊＊	719.376^＊＊

图6 各组A549细胞中CBX4蛋白表达 A：Control组；B：miR-NC组；C：miR-671-5p组；D：miR-671-5p+pcDNA组；E：miR-671-5p+CBX4组。

Fig.6 Expression of CBX4 protein in A549 cells of each group

图7 各组NSCLC细胞凋亡、迁移和侵袭情况（结晶紫染色，×200）

Fig.7 Apoptosis, migration and invasion of NSCLC cells in each group(crystal violet staining, ×200)

表4 各组NSCLC细胞活力、克隆形成数、凋亡率、迁移和侵袭细胞数比较（n=6，$\bar{x}±s$）

Tab.4 Comparison of NSCLC cell viability, number of clone formation, apoptosis rate, migration and number of invasive cells between the five groups

组别	CBX4 mRNA	CBX4蛋白	细胞活力（OD值）	克隆细胞数	凋亡率（%）	迁移细胞数	侵袭细胞数
Control组	1.00±0.02	1.00±0.03	1.09±0.15	97.68±5.49	8.24±0.13	86.34±3.52	78.69±2.63
miR-NC组	0.99±0.03	1.01±0.05	1.07±0.13	97.75±5.63	8.26±0.15	86.38±3.61	78.72±2.62
miR-671-5p组	0.36±0.03^ab	0.33±0.02^ab	0.46±0.05^ab	39.54±2.16^ab	34.52±2.31^ab	40.15±2.03^ab	35.42±1.89^ab
miR-671-5p+pcDNA组	0.37±0.02	0.32±0.04	0.48±0.06	39.57±2.13	34.39±2.46	40.19±2.05	35.51±1.92
miR-671-5p+CBX4组	0.84±0.05^cd	0.81±0.05^cd	1.03±0.11^cd	82.36±4.25^cd	13.64±1.02^cd	81.23±3.12^cd	67.49±2.01^cd
F	613.941^＊＊	455.051^＊＊	55.276^＊＊	297.408^＊＊	441.727^＊＊	412.551^＊＊	585.024^＊＊

图8 各组A549细胞中CBX4蛋白表达 A：Control组；B：si-NC组；C：si-CircCDR1as组；D：si-CircCDR1as+anti-miR-NC组；E：si-CircCDR1as+anti-miR-671-5p组。

Fig.8 CBX4 protein expression in A549 cells of each group

表5 各组NSCLC细胞CBX4表达的比较（n=6，$\bar{x}±s$）

Tab.5 Comparison of CBX4 expression in NSCLC cells between the five groups

组别	CBX4 mRNA	CBX4蛋白
Control组	1.00±0.03	1.00±0.02
si-NC组	1.02±0.05	1.01±0.03
si-CircCDR1as组	0.43±0.03^ab	0.49±0.05^ab
si-CircCDR1as+anti-miR-NC组	0.41±0.02	0.50±0.07
si-CircCDR1as+anti-miR-671-5p组	0.82±0.06^cd	0.87±0.09^cd
F	322.880^＊＊	121.304^＊＊

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CircCDR1as调节miR-671-5p/CBX4轴对NSCLC细胞生物学行为的影响

Effects of CircCDR1as on the biological behavior of NSCLC cells by regulating the miR-671-5p/CBX4 axis

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