PDZ连接激酶诱导自噬对肺癌细胞顺铂化疗敏感性的影响研究

doi:10.3877/cma.j.issn.2095-1221.2021.04.005

目的

探究PDZ连接激酶（PBK）对肺癌细胞顺铂化疗敏感性的作用及其相关的作用机制。

方法

A549细胞用顺铂处理或者是转染si-NC、si-PBK、si-亲嗜性病毒整合位点-1 （EVI1）、oe-NC和oe-EVI1。RT-qPCR检测人肺癌细胞株A549、HCC827、NCI-H1299和人正常肺上皮细胞BEAS-2B中EVI1和PBK mRNA表达；Western blot检测细胞中EVI1、PBK、Beclin1、p62和微管相关蛋白1轻链3 （LC3B）蛋白表达；CCK-8检测细胞活力；EdU实验检测细胞增殖；Transwell实验检测细胞迁移和侵袭；ChIP-PCR实验检测细胞中EVI1和PBK启动子区域的结合。多组间比较采用单因素方差分析，组间两两比较（EVI1及PBK表达情况只比较HCC827组与BEAS-2B组、NCI-H1299组与BEAS-2B组、A549组与BEAS-2B组）采用LSD-t检验。si-NC组和si-EVI1、oe-NC组和oe-EVI1组PBK的表达情况采用独立样本t检验进行比较。

结果

与BEAS-2B细胞相比，HCC827、NCI-H1299和A549细胞中EVI1和PBK mRNA表达以及蛋白表达均升高，差异具有统计学意义（P均< 0.05）。与空白对照组相比，顺铂组和顺铂+si-NC组细胞中EVI1和PBK mRNA表达以及蛋白表达均升高，Beclin1和LC3Ⅱ/ LC3Ⅰ蛋白表达（0.15±0.01比0.36±0.02、0.34±0.02）（1.32±0.11比4.16±0.21、4.04±0.15）均升高，差异具有统计学意义（P均< 0.05）；与空白对照组相比，顺铂组、顺铂+si-NC组及顺铂+si-PBK组细胞24、48、72 h细胞活力降低，EdU阳性细胞率[（42.71±2.56）﹪比（30.25±1.91）﹪、（28.90±2.51）﹪]、迁移数[（133.67±6.51）个比（72.00±4.00）个、（70.00±2.65）个]、侵袭数[（81.00±4.00）个比（43.00±3.00）个、（42.00±3.00）个]、p62蛋白表达（0.65±0.03比0.22±0.02、0.23±0.01）均降低，差异具有统计学意义（P均< 0.05）。与顺铂组和顺铂+si-NC组相比，顺铂+si-PBK组细胞中PBK mRNA和蛋白表达降低，24、48、72 h细胞活力降低，EdU阳性细胞率[（30.25±1.91）﹪比（28.90±2.51）﹪、（22.25±1.97）﹪]、迁移数[（72.00±4.00）个、（70.00±2.65）个比（34.00±3.00）个]、侵袭数[（43.00±3.00）个、（42.00±3.00）个比（21.33± 2.52）个]、Beclin1和LC3Ⅱ/ LC3Ⅰ蛋白表达（0.36±0.02、0.34±0.02比0.25±0.02）（4.16±0.21、4.04±0.15比2.45±0.22）均降低，差异具有统计学意义（P均< 0.05）；p62蛋白表达（0.22±0.02、0.23±0.01比0.46±0.02）升高，差异具有统计学意义（P < 0.05）。EVI1通过直接与PBK启动子区域结合，与si-NC组相比，si-EVI1组细胞中EVI1 mRNA和蛋白表达降低，PBK mRNA和蛋白表达降低，差异具有统计学意义（P均< 0.05）；与oe-NC组相比，oe-EVI1组细胞中EVI1和PBK mRNA和蛋白表达升高，差异具有统计学意义（P均< 0.05）。

结论

受EVI1调节的PBK可能通过促进自噬抑制肺癌细胞对顺铂的化疗敏感性。

关键词: 肺癌, PDZ连接激酶, 亲嗜性病毒整合位点-1, 自噬, 顺铂

Objective

To investigate the effect of PDZ binding kinase (PBK) on the chemosensitivity of lung cancer cells to cisplatin and its related mechanism.

Methods

A549 cells were treated with cisplatin or transfected with si-NC, si-PBK, si-EVI1, oe-NC and oe-EVI1. The mRNA expressions of ecotropic viral integration site-1 (EVI1) and PBK in human lung cancer cell lines A549, HCC827, NCI-H1299 and BEAS-2B were detected by RT-qPCR; The protein expressions of EVI1, PBK, Beclin1, p62 and microtubule associated protein 1 light chain 3 (LC3B) were detected by Western blot; Cell viability was detected by CCK-8; cell proliferation was detected by EdU assay; Migration and invasion of cells were detected by Transwell assay; The binding of EVI1 and PBK promoter region was detected by ChIP-PCR. One-way analysis of variance was used to compare the difference among multiple groups, and LSD-t test was used to comparethe difference in the expression of EVI1 and PBK between HCC827 group and BEAS-2B group, NCI-H1299 group and BEAS-2B group, A549 and BEAS-2B group. Independent sample t-test was used to compare the difference in the expression of PBK between si-NC group and si-EVI1 group, oe-NC group and oe-EVI1 group.

Results

Compared with BEAS-2B cells, the expression of EVI1 and PBK mRNA and protein in HCC827, NCI-H1299 and A549 cells increased, and the difference was statistically significant (all P < 0.05) . Compared with the blank control group, the expression of EVI1 and PBK mRNA and protein were incread in the cells of the cisplatin group and the cisplatin+si-NC group, and the protein expression of Beclin1 and LC3Ⅱ/LC3Ⅰ (0.15±0.01 vs 0.36±0.02, 0.34±0.02) (1.32±0.11 vs 4.16±0.21, 4.04±0.15) was increased, the difference was statistically significant (P < 0.05) ; Howerer cell viability decreased at 24, 48, and 72 h, the rate of EdU positive cells [ (42.71±2.56) ﹪ vs (30.25±1.91) ﹪, (28.90±2.51) ﹪], migration number (133.67±6.51 vs 72.00±4.00, 70.00±2.65) , the number of invasions (81.00±4.00 vs 43.00±3.00, 42.00±3.00) decreased, the expression of p62 protein (0.65±0.03 vs 0.22±0.02, 0.23±0.01) were decreased, and the differences were statistically significant (all P < 0.05) . Compared with the cisplatin group and the cisplatin+si-NC group, the expression of PBK mRNA and protein was decreased in the cisplatin+si-PBK group decreased, and the cell viability was also decreased at 24, 48, and 72 h. The rate of EdU positive cells was [ (30.25±1.91) ﹪ vs (28.90±2.51) ﹪, (22.25±1.97) ﹪], migration number (72.00±4.00, 70.00±2.65 vs 34.00±3.00) , invasion number (43.00±3.00, 42.00±3.00 vs 21.33±2.52) , the expression of Beclin1 and LC3Ⅱ/LC3Ⅰ protein (0.36±0.02, 0.34±0.02 vs 0.25±0.02) (4.16±0.21, 4.04±0.15 vs 2.45±0.22) were decreased, and the difference were statistically significant (all P < 0.05) ; The expression of p62 protein (0.22±0.02, 0.23±0.01 vs 0.46±0.02) was increased, and the difference was statistically significant (P < 0.05) . Compared with the si-NC group, EVI1 directly binds to the PBK promoter region. Compared with the si-NC group, the expression of EVI1 and PBK mRNA and protein was decreased in the cells of the si-EVI1 group, and the difference was statistically significant (all P < 0.05) ; Compared with the oe-NC group, the expression of EVI1 and PBK mRNA and protein was increased in the cells of the oe-EVI1 group, and the difference was statistically significant (all P <0.05) .

Conclusion

PBK regulated by EVI1 may inhibit the chemotherapy sensitivity of lung cancer cells to cisplatin by promoting autophagy.

Key words: Lung cancer, PDZ-binding kinase, Ecotropic viral integration site-1, Autophagy, Cisplatin

表1 引物序列信息

基因	引物序列（5'→3'）	预期扩增产物长度（bp）
EVI1	上游CTCAGCATTTTCAATGGTTGA	147
	下游TGTGACAGCATGTGTTTCTCC
PBK	上游TATGGCAAGAGGGTTAAAGTATCTGC	176
	下游CAATGTAACAAGCCTCAGGGTCAG
GAPDH	上游GGTCACCAGGGCTGCTTTTA	141
	下游GGATCTCGCTCCTGGAAGATG

表1 引物序列信息

基因	引物序列（5'→3'）	预期扩增产物长度（bp）
EVI1	上游CTCAGCATTTTCAATGGTTGA	147
	下游TGTGACAGCATGTGTTTCTCC
PBK	上游TATGGCAAGAGGGTTAAAGTATCTGC	176
	下游CAATGTAACAAGCCTCAGGGTCAG
GAPDH	上游GGTCACCAGGGCTGCTTTTA	141
	下游GGATCTCGCTCCTGGAAGATG

图1 Western blot检测细胞中EVI1和PBK蛋白表达

表2 人正常肺上皮细胞和人肺癌细胞中EVI1和PBK的表达（ ± s，n=3）

分组	EVI1 mRNA表达	EVI1蛋白表达	PBK mRNA表达	PBK蛋白表达
BEAS-2B	1.00±0.05	0.18±0.01	1.00±0.06	0.15±0.01
HCC827	2.23±0.22^a	0.32±0.01^a	2.54±0.20^a	0.29±0.01^a
NCI-H1299	2.65±0.15^a	0.35±0.02^a	2.75±0.13^a	0.36±0.02^a
A549	2.88±0.15^a	0.51±0.02^a	3.22±0.19^a	0.57±0.03^a
F值	88.129	209.967	113.865	248.899
P值	< 0.001	< 0.001	< 0.001	< 0.001

表2 人正常肺上皮细胞和人肺癌细胞中EVI1和PBK的表达（ ± s，n=3）

分组	EVI1 mRNA表达	EVI1蛋白表达	PBK mRNA表达	PBK蛋白表达
BEAS-2B	1.00±0.05	0.18±0.01	1.00±0.06	0.15±0.01
HCC827	2.23±0.22^a	0.32±0.01^a	2.54±0.20^a	0.29±0.01^a
NCI-H1299	2.65±0.15^a	0.35±0.02^a	2.75±0.13^a	0.36±0.02^a
A549	2.88±0.15^a	0.51±0.02^a	3.22±0.19^a	0.57±0.03^a
F值	88.129	209.967	113.865	248.899
P值	< 0.001	< 0.001	< 0.001	< 0.001

图2 Western blot检测A549细胞中PBK蛋白表达

表3 顺铂处理和敲低PBK对A549细胞中PBK表达的影响（ ± s，n=3）

分组	PBK mRNA表达	PBK蛋白表达
空白对照	1.00±0.06	0.46±0.02
顺铂	2.24±0.11^a	0.89±0.02^a
顺铂+si-NC	2.29±0.10^a	0.88±0.03^a
顺铂+si- PBK	0.34±0.02^abc	0.18±0.01^abc
F值	399.108	496.115
P值	< 0.001	< 0.001

表3 顺铂处理和敲低PBK对A549细胞中PBK表达的影响（ ± s，n=3）

分组	PBK mRNA表达	PBK蛋白表达
空白对照	1.00±0.06	0.46±0.02
顺铂	2.24±0.11^a	0.89±0.02^a
顺铂+si-NC	2.29±0.10^a	0.88±0.03^a
顺铂+si- PBK	0.34±0.02^abc	0.18±0.01^abc
F值	399.108	496.115
P值	< 0.001	< 0.001

图3 荧光显微镜下观察A549细胞增殖（×100）

表4 敲低PBK对A549细胞活力的影响（ ± s，n=3）

分组	A450 nm值
分组	0 h	24 h	48 h	72 h
空白对照	0.25±0.01	0.42±0.03	0.79±0.04	1.33±0.06
顺铂	0.24±0.02	0.34±0.02^a	0.56±0.03^a	0.79±0.05^a
顺铂+si-NC	0.26±0.02	0.33±0.02^a	0.54±0.03^a	0.78±0.03^a
顺铂+si- PBK	0.25±0.01	0.27±0.01^abc	0.40±0.02^abc	0.55±0.03^abc
F组间值	0.032	25.945	48.264	97.369
P值	0.992	<0.001	<0.001	<0.001

表4 敲低PBK对A549细胞活力的影响（ ± s，n=3）

分组	A450 nm值
分组	0 h	24 h	48 h	72 h
空白对照	0.25±0.01	0.42±0.03	0.79±0.04	1.33±0.06
顺铂	0.24±0.02	0.34±0.02^a	0.56±0.03^a	0.79±0.05^a
顺铂+si-NC	0.26±0.02	0.33±0.02^a	0.54±0.03^a	0.78±0.03^a
顺铂+si- PBK	0.25±0.01	0.27±0.01^abc	0.40±0.02^abc	0.55±0.03^abc
F组间值	0.032	25.945	48.264	97.369
P值	0.992	<0.001	<0.001	<0.001

表5 敲低PBK对A549细胞增殖的影响（ ± s，n=3）

分组	EdU阳性细胞率（﹪）
空白对照	42.71±2.56
顺铂	30.25±1.91^a
顺铂+si-NC	28.90±2.51^a
顺铂+si- PBK	22.25±1.97^abc
F值	42.904
P值	< 0.001

表5 敲低PBK对A549细胞增殖的影响（ ± s，n=3）

分组	EdU阳性细胞率（﹪）
空白对照	42.71±2.56
顺铂	30.25±1.91^a
顺铂+si-NC	28.90±2.51^a
顺铂+si- PBK	22.25±1.97^abc
F值	42.904
P值	< 0.001

图4 光学显微镜下观察敲低PBK对A549细胞迁移和侵袭的影响（结晶紫染色，×200）

表6 敲低PBK对A549细胞迁移和侵袭的影响（ ± s，n=3）

分组	迁移数（个）	侵袭数（个）
空白对照	133.67±6.51	81.00±4.00
顺铂	72.00±4.00^a	43.00±3.00^a
顺铂+si-NC	70.00±2.65^a	42.00±3.00^a
顺铂+si- PBK	34.00±3.00^abc	21.33±2.52^abc
F值	276.238	184.033
P值	< 0.001	< 0.001

表6 敲低PBK对A549细胞迁移和侵袭的影响（ ± s，n=3）

分组	迁移数（个）	侵袭数（个）
空白对照	133.67±6.51	81.00±4.00
顺铂	72.00±4.00^a	43.00±3.00^a
顺铂+si-NC	70.00±2.65^a	42.00±3.00^a
顺铂+si- PBK	34.00±3.00^abc	21.33±2.52^abc
F值	276.238	184.033
P值	< 0.001	< 0.001

图5 Western blot检测敲低PBK对A549细胞自噬的影响

表7 敲低PBK对A549细胞自噬的影响（ ± s，n =3）

分组	Beclin1蛋白表达	p62蛋白表达	LC3Ⅱ/ LC3Ⅰ蛋白表达
空白对照	0.15±0.01	0.65±0.03	1.32±0.11
顺铂	0.36±0.02^a	0.22±0.02^a	4.16±0.21^a
顺铂+si-NC	0.34±0.02^a	0.23±0.01^a	4.04±0.15^a
顺铂+si- PBK	0.25±0.02^abc	0.46±0.02^abc	2.45±0.22^abc
F值	85.222	320.363	176.250
P值	< 0.001	< 0.001	< 0.001

表7 敲低PBK对A549细胞自噬的影响（ ± s，n =3）

分组	Beclin1蛋白表达	p62蛋白表达	LC3Ⅱ/ LC3Ⅰ蛋白表达
空白对照	0.15±0.01	0.65±0.03	1.32±0.11
顺铂	0.36±0.02^a	0.22±0.02^a	4.16±0.21^a
顺铂+si-NC	0.34±0.02^a	0.23±0.01^a	4.04±0.15^a
顺铂+si- PBK	0.25±0.02^abc	0.46±0.02^abc	2.45±0.22^abc
F值	85.222	320.363	176.250
P值	< 0.001	< 0.001	< 0.001

图6 EVI1通过与PBK启动子区结合调控PBK表达

表8 敲低PBK对A549细胞EVI1表达的影响（ ± s，n=3）

分组	EVI1 mRNA表达	EVI1蛋白表达
空白对照	1.00±0.04	0.32±0.02
顺铂	2.34±0.14^a	0.55±0.03^a
顺铂+si-NC	2.30±0.12^a	0.55±0.02^a
顺铂+si- PBK	2.35±0.10^a	0.56±0.03^a
F值	118.875	62.633
P值	< 0.001	< 0.001

表8 敲低PBK对A549细胞EVI1表达的影响（ ± s，n=3）

分组	EVI1 mRNA表达	EVI1蛋白表达
空白对照	1.00±0.04	0.32±0.02
顺铂	2.34±0.14^a	0.55±0.03^a
顺铂+si-NC	2.30±0.12^a	0.55±0.02^a
顺铂+si- PBK	2.35±0.10^a	0.56±0.03^a
F值	118.875	62.633
P值	< 0.001	< 0.001

表9 敲低EVI1和过表达EVI1对PBK表达的影响（ ± s，n=3）

分组	EVI1 mRNA表达	EVI1蛋白表达	PBK mRNA表达	PBK蛋白表达
si-NC	1.00±0.06	0.46±0.03	1.00±0.04	0.56±0.03
si- EVI1	0.38±0.03	0.29±0.02	0.36±0.02	0.32±0.02
t值	16.008	8.167	24.787	11.529
P值	< 0.001	0.001	< 0.001	< 0.001
oe-NC	1.03±0.07	0.47±0.02	1.06±0.07	0.60±0.03
oe- EVI1	2.25±0.08	2.17±0.14	2.08±0.12	2.34±0.11
t值	19.878	20.821	12.717	26.432
P值	< 0.001	< 0.001	< 0.001	< 0.001

表9 敲低EVI1和过表达EVI1对PBK表达的影响（ ± s，n=3）

分组	EVI1 mRNA表达	EVI1蛋白表达	PBK mRNA表达	PBK蛋白表达
si-NC	1.00±0.06	0.46±0.03	1.00±0.04	0.56±0.03
si- EVI1	0.38±0.03	0.29±0.02	0.36±0.02	0.32±0.02
t值	16.008	8.167	24.787	11.529
P值	< 0.001	0.001	< 0.001	< 0.001
oe-NC	1.03±0.07	0.47±0.02	1.06±0.07	0.60±0.03
oe- EVI1	2.25±0.08	2.17±0.14	2.08±0.12	2.34±0.11
t值	19.878	20.821	12.717	26.432
P值	< 0.001	< 0.001	< 0.001	< 0.001

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Effect of autophagy induced by PDZ binding kinase on chemosensitivity of lung cancer cells to cisplatin

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Effect of autophagy induced by PDZ binding kinase on chemosensitivity of lung cancer cells to cisplatin