敲减circSERPINE2通过靶向调控miR-34a-5p表达抑制滋养层细胞增殖、迁移和侵袭

doi:10.3877/cma.j.issn.2095-1221.2023.04.001

目的

探讨circSERPINE2对滋养层细胞HTR8/SVneo增殖、迁移和侵袭的影响和可能机制。

方法

收集37例子痫前期患者胎盘组织和37例正常妊娠孕妇胎盘组织。体外培养滋养层细胞HTR8/Svneo，转染circSERPINE2小干扰RNA （si-circSERPINE2）或miR-34a-5p模拟物、或共转染circSERPINE2小干扰RNA与miR-34a-5p抑制剂至HTR8/Svneo细胞。qRT-PCR法检测circSERPINE2和miR-34a-5p表达；CCK-8法和克隆形成实验检测细胞增殖；划痕实验、Transwell和Western blot法分别检测细胞迁移、侵袭及细胞中E-cadherin和N-cadherin表达。双荧光素酶报告基因实验证实circSERPINE2和miR-34a-5p的靶向关系。两组间比较采用配对样本t检验或独立样本t检验；多组间比较采用单因素方差分析，组间两两比较采用LSD-t检验。

结果

与正常胎盘组织比较，子痫前期患者胎盘组织中circSERPINE2的表达（0.37 ± 0.04比1.00 ± 0.11）降低，miR-34a-5p的表达（3.50 ± 0.28比1.00 ± 0.08）升高，差异有统计学意义（P均< 0.05）。与si-NC比较，si-circSERPINE2的HTR8/Svneo细胞中circSERPINE2表达水平（0.31 ± 0.03比1.01 ± 0.06）、细胞活力、克隆形成数、侵袭数、划痕愈合率及N-cadherin表达下降，E-cadherin表达增高（P均< 0.05）；与miR-NC比较，转染miR-34a-5p的HTR8/Svneo细胞活力、克隆形成数、侵袭数、划痕愈合率及N-cadherin表达下降，miR-34a-5p （3.48 ± 0.32比1.00 ± 0.00）、E-cadherin表达增高（P均< 0.05）。circSERPINE2靶向负调控miR-34a-5p。下调miR-34a-5p可逆转敲减circSERPINE2对HTR8/Svneo细胞增殖、迁移和侵袭的抑制作用。

结论

circSERPINE2在子痫前期患者胎盘组织中表达下调，敲减circSERPINE2可能通过靶向负调控miR-34a-5p表达抑制滋养层细胞增殖、迁移和侵袭。

关键词: 子痫前期, 滋养层细胞, circSERPINE2, miR-34a-5p

Objective

To explore the effect and possible mechanism of circSERPINE2 on the proliferation, migration and invasion of trophoblast cells HTR8/SVneo.

Methods

The placental tissues of 37 patients with preeclampsia and 37 normal pregnant women were collected. Trophoblast cells HTR8/Svneo were cultured in vitro and transfected with circSERPINE2 small interfering RNA (si-circSERPINE2) or miR-34a-5p mimic or co-transfected with si-circSERPINE2 and miR-34a-5p inhibitor into HTR8/Svneo cells. The expression of circSERPINE2 and miR-34a-5p was defected by qRT-PCR. Cell proliferation was detected by CCK-8 assay and colony formation assay. Cell migration, invasion and expression of E-cadherin and N-cadherin were detected by scratch assay, Transwell assay and Western blot, respectively. Dual-luciferase reporter gene experiment confirmed the targeting relationship between circSERPINE2 and miR-34a-5p. A paired sample t-test or independent sample t-test was used to compare between two groups.One-way analysis of variance was used for multi-group comparison, and the LSD-t test was used for pairwise comparison between groups.

Results

Compared with normal placental tissues, the expression of circSERPINE2 was decreased in the placental tissue of patients with preeclampsia (0.37 ± 0.04 vs 1.00 ± 0.11) ;the expression of miR-34a-5p was increased (3.50 ± 0.28 vs 1.00 ± 0.08) , and the differences were statistically significant (all P < 0.05) . Compared with the si-NC, the circSERPINE2 expression level (0.31 ± 0.03 vs 1.01 ± 0.06) , cell viability, number of clones, number of invasions, scratch healing rate and N-cadherin expression were decreased in the HTR8/Svneo cells transfected with si-circSERPINE2, but the expression of E-cadherin was increased (P < 0.05) . Compared with miR-NC, cell viability, number of clones formed, number of invasions, scratch healing rate and N-cadherin expression were decreased in HTR8/Svneo cells transfected with miR-34a-5p mimic, the expression of miR-34a-5p (3.48 ± 0.32 vs 1.00 ± 0.00) and E-cadherin were increased (all P < 0.05) . circSERPINE2 targeted and negatively regulated miR-34a-5p. Down-regulating miR-34a-5p reversed the inhibitory effect of circSERPINE2 knockdown on HTR8/Svneo cells proliferation, migration and invasion.

Conclusion

circSERPINE2 is down-regulated in placental tissue of preeclampsia patients, and knockdown of circSERPINE2 may inhibit the proliferation, migration and invasion of trophoblast cells by targeting and negatively regulating miR-34a-5p expression.

Key words: Preeclampsia, Trophoblast cells, circSERPINE2, miR-34a-5p

表1 引物序列信息

基因	序列（5'→3'）	预期扩增产物长度（bp）
circSERPINE2	上游CCCGAGAACACAAAGAAACGC	217
	下游AAGAGGGGGAGATGCCAGTT
GAPDH	上游TCGGAGTCAACGGATTTGGT	89
	下游TTCCCGTTCTCAGCCTTGAC
miR-34a-5p	上游CCCACATTTCCTTCTTATCAACAG	183
	下游GGCATCTCTCGCTTCATCTT
U6	上游TGCGGGTGCTCGCTTCGCAGC	91
	下游CCAGTGCAGGGTCCGAGGT

表1 引物序列信息

基因	序列（5'→3'）	预期扩增产物长度（bp）
circSERPINE2	上游CCCGAGAACACAAAGAAACGC	217
	下游AAGAGGGGGAGATGCCAGTT
GAPDH	上游TCGGAGTCAACGGATTTGGT	89
	下游TTCCCGTTCTCAGCCTTGAC
miR-34a-5p	上游CCCACATTTCCTTCTTATCAACAG	183
	下游GGCATCTCTCGCTTCATCTT
U6	上游TGCGGGTGCTCGCTTCGCAGC	91
	下游CCAGTGCAGGGTCCGAGGT

图1 circSERPINE2和miR-34a-5p在子痫前期胎盘组织中的表达（n = 37）注：a图为circSERPINE2相对表达量；b图为miR-34a-5p相对表达量；与正常胎盘组织比较，^aP < 0.05

图2 来自宿主基因SERPINE2的circSERPINE2反向剪接

图3 circSERPINE2在滋养层细胞HTR8/Svneo中的表达注：与si-NC比较，^aP < 0.05

表1 RNase R实验确定circSERPINE2的环状性质（ ± s）

分组	实验次数	circSERPINE	SERPINE	GAPDH
mock	3	1.02 ± 0.08	1.01 ± 0.06	1.00 ± 0.07
Rnase R	3	0.98 ± 0.07	0.18 ± 0.03	0.15 ± 0.03
t值		1.129	37.119	33.483
P值		0.276	< 0.001	< 0.001

表1 RNase R实验确定circSERPINE2的环状性质（ ± s）

分组	实验次数	circSERPINE	SERPINE	GAPDH
mock	3	1.02 ± 0.08	1.01 ± 0.06	1.00 ± 0.07
Rnase R	3	0.98 ± 0.07	0.18 ± 0.03	0.15 ± 0.03
t值		1.129	37.119	33.483
P值		0.276	< 0.001	< 0.001

图4 敲减circSERPINE2对HTR8/Svneo细胞增殖和侵袭的影响（结晶紫染色）注：a ~ c图分别为空白对照、si-NC和si-circSERPINE2的细胞克隆形成情况；d ~ f图为Transwell分别检测空白对照、si-NC和si-circSERPINE2细胞侵袭情况（×400）

图5 划痕愈合实验检测细胞迁移（×40）注：a ~ c图为分别为0 h空白对照、si-NC和si-circSERPINE2的细胞迁移情况；d ~ f图分别为24 h空白对照、si-NC和si-circSERPINE2的细胞迁移情况

图6 Western blot检测E-cadherin和N-cadherin蛋白表达

表2 敲减circSERPINE2对HTR8/Svneo细胞增殖、迁移和侵袭的影响（ ± s）

分组	实验次数	circSERPINE2	细胞活力（A450 nm）	细胞克隆形成数（个）	划痕愈合率（%）	侵袭细胞数（个）	E-cadherin蛋白	N-cadherin蛋白
空白对照	3	1.00 ± 0.00	0.75 ± 0.05	84.69 ± 8.11	63.15 ± 6.05	119.24 ± 11.85	0.14 ± 0.02	0.70 ± 0.05
si-NC	3	1.01 ± 0.06	0.73 ± 0.06	82.78 ± 7.54	61.77 ± 5.41	116.91 ± 12.03	0.16 ± 0.02	0.68 ± 0.04
si-circSERPINE2	3	0.31 ± 0.03^ab	0.36 ± 0.03^ab	41.84 ± 4.11^ab	24.77 ± 2.65^ab	50.88 ± 4.08^ab	0.57 ± 0.04^ab	0.25 ± 0.02^ab
F值		966.200	186.043	113.402	175.568	134.773	662.625	387.800
P值		< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

表2 敲减circSERPINE2对HTR8/Svneo细胞增殖、迁移和侵袭的影响（ ± s）

分组	实验次数	circSERPINE2	细胞活力（A450 nm）	细胞克隆形成数（个）	划痕愈合率（%）	侵袭细胞数（个）	E-cadherin蛋白	N-cadherin蛋白
空白对照	3	1.00 ± 0.00	0.75 ± 0.05	84.69 ± 8.11	63.15 ± 6.05	119.24 ± 11.85	0.14 ± 0.02	0.70 ± 0.05
si-NC	3	1.01 ± 0.06	0.73 ± 0.06	82.78 ± 7.54	61.77 ± 5.41	116.91 ± 12.03	0.16 ± 0.02	0.68 ± 0.04
si-circSERPINE2	3	0.31 ± 0.03^ab	0.36 ± 0.03^ab	41.84 ± 4.11^ab	24.77 ± 2.65^ab	50.88 ± 4.08^ab	0.57 ± 0.04^ab	0.25 ± 0.02^ab
F值		966.200	186.043	113.402	175.568	134.773	662.625	387.800
P值		< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

图7 Western blot检测E-cadherin和N-cadherin蛋白表达

图8 上调miR-34a-5p对HTR8/Svneo细胞增殖和侵袭的影响（结晶紫染色）注：a ~ b图分别为miR-NC和miR-34a-5p的细胞克隆形成情况；c ~ d图为Transwell分别检测miR-NC和miR-34a-5p的细胞侵袭（× 400）

图9 上调miR-34a-5p对HTR8/Svneo细胞迁移的影响（× 40）注：a ~ b图分别为0 h miR-NC和miR-34a-5p的细胞迁移情况；c ~ d图分别为24 h miR-NC和miR-34a-5p的细胞迁移情况

表3 上调miR-34a-5p对HTR8/Svneo细胞增殖、迁移和侵袭的影响（ ± s）

分组	实验次数	miR-34a-5p	细胞活力（A450 nm）	细胞克隆形成数（个）	划痕愈合率（%）	侵袭细胞数（个）	E-cadherin蛋白	N-cadherin蛋白
miR-NC	3	1.00 ± 0.00	0.74 ± 0.06	84.65 ± 6.69	63.69 ± 6.05	117.51 ± 12.94	0.15 ± 0.02	0.69 ± 0.05
miR-34a-5p	3	3.48 ± 0.32	0.43 ± 0.04	49.13 ± 4.68	30.54 ± 3.15	62.11 ± 5.65	0.51 ± 0.04	0.31 ± 0.03
t值		23.250	12.897	13.052	14.580	11.771	24.150	19.551
P值		< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

表3 上调miR-34a-5p对HTR8/Svneo细胞增殖、迁移和侵袭的影响（ ± s）

分组	实验次数	miR-34a-5p	细胞活力（A450 nm）	细胞克隆形成数（个）	划痕愈合率（%）	侵袭细胞数（个）	E-cadherin蛋白	N-cadherin蛋白
miR-NC	3	1.00 ± 0.00	0.74 ± 0.06	84.65 ± 6.69	63.69 ± 6.05	117.51 ± 12.94	0.15 ± 0.02	0.69 ± 0.05
miR-34a-5p	3	3.48 ± 0.32	0.43 ± 0.04	49.13 ± 4.68	30.54 ± 3.15	62.11 ± 5.65	0.51 ± 0.04	0.31 ± 0.03
t值		23.250	12.897	13.052	14.580	11.771	24.150	19.551
P值		< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

图10 circSERPINE2与miR-34a-5p互补的核苷酸序列

图11 circSERPINE2调控miR-34a-5p的表达注：与pcDNA比较，^aP < 0.05；与si-NC比较，^bP < 0.05

表4 荧光素酶相对活性（ ± s）

分组	实验次数	WT-circSERPINE2	MUT-circSERPINE2
miR-NC	3	1.03 ± 0.08	1.04 ± 0.06
miR-34a-5p	3	0.51 ± 0.04	1.01 ± 0.05
t值		17.441	1.152
P值		< 0.001	0.266

表4 荧光素酶相对活性（ ± s）

分组	实验次数	WT-circSERPINE2	MUT-circSERPINE2
miR-NC	3	1.03 ± 0.08	1.04 ± 0.06
miR-34a-5p	3	0.51 ± 0.04	1.01 ± 0.05
t值		17.441	1.152
P值		< 0.001	0.266

图12 Western blot检测E-cadherin和N-cadherin蛋白表达

图13 下调miR-34a-5p逆转敲减circSERPINE2对HTR8/Svneo细胞增殖和侵袭的影响（结晶紫染色）注：a ~ b图为si-circSERPINE2+anti-miR-NC和si-circSERPINE2+anti-miR-34a-5p细胞克隆形成情况；c ~ d图为Transwell分别检测si-circSERPINE2+ anti-miR-NC和si-circSERPINE2+anti-miR-34a-5p细胞侵袭

图14 下调miR-34a-5p逆转敲减circSERPINE2对HTR8/Svneo细胞迁移的影响（× 40）注：a ~ b图为0 h si-circSERPINE2+anti-miR-NC和si-circSERPINE2+anti-miR-34a-5p迁移情况；c ~ d图为24 h si-circSERPINE2+anti-miR-NC和si-circSERPINE2+anti-miR-34a-5p迁移情况

表5 下调miR-34a-5p逆转敲减circSERPINE2对HTR8/Svneo细胞增殖、迁移和侵袭的作用（ ± s）

分组	实验次数	miR-34a-5p	细胞活力（A₄₅₀ nm）	细胞克隆形成数（个）	划痕愈合率（%）
si-circSERPINE2+anti-miR-NC	3	1.00 ± 0.00	0.33 ± 0.03	40.93 ± 4.08	22.83 ± 2.51
si-circSERPINE2+anti-miR-34a-5p	3	0.34 ± 0.03	0.64 ± 0.05	73.14 ± 6.37	52.64 ± 4.62
t值		66.000	15.949	12.774	17.009
P值		< 0.001	< 0.001	< 0.001	< 0.001
分组	实验次数	侵袭细胞数（个）	E-cadherin蛋白	N-cadherin蛋白
si-circSERPINE2+anti-miR-NC	3	51.69 ± 5.31	0.58 ± 0.04	0.24 ± 0.02
si-circSERPINE2+anti-miR-34a-5p	3	99.79 ± 6.88	0.28 ± 0.02	0.59 ± 0.05
t值		16.604	20.125	19.498
P值		< 0.001	< 0.001	< 0.001

表5 下调miR-34a-5p逆转敲减circSERPINE2对HTR8/Svneo细胞增殖、迁移和侵袭的作用（ ± s）

分组	实验次数	miR-34a-5p	细胞活力（A₄₅₀ nm）	细胞克隆形成数（个）	划痕愈合率（%）
si-circSERPINE2+anti-miR-NC	3	1.00 ± 0.00	0.33 ± 0.03	40.93 ± 4.08	22.83 ± 2.51
si-circSERPINE2+anti-miR-34a-5p	3	0.34 ± 0.03	0.64 ± 0.05	73.14 ± 6.37	52.64 ± 4.62
t值		66.000	15.949	12.774	17.009
P值		< 0.001	< 0.001	< 0.001	< 0.001
分组	实验次数	侵袭细胞数（个）	E-cadherin蛋白	N-cadherin蛋白
si-circSERPINE2+anti-miR-NC	3	51.69 ± 5.31	0.58 ± 0.04	0.24 ± 0.02
si-circSERPINE2+anti-miR-34a-5p	3	99.79 ± 6.88	0.28 ± 0.02	0.59 ± 0.05
t值		16.604	20.125	19.498
P值		< 0.001	< 0.001	< 0.001

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Knockdown of circSERPINE2 inhibits trophoblast cell proliferation, migration and invasion by targeting miR-34a-5p expression

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Knockdown of circSERPINE2 inhibits trophoblast cell proliferation, migration and invasion by targeting miR-34a-5p expression