IGF2BP2/CCNB2轴促进三阴性乳腺癌进展的机制研究

doi:10.3877/cma.j.issn.1674-0807.2025.05.005

目的

研究m⁶A依赖的IGF2BP2/CCNB2轴在三阴性乳腺癌（TNBC）进展中的作用和机制。

方法

选取2020年5月至2023年4月在陆军军医大学第一附属医院乳腺甲状腺外科接受手术的30例TNBC患者癌组织和癌旁组织标本，以及人正常乳腺上皮细胞MCF-10A及TNBC细胞系（MDA-MB-231、MDA-MB-468、BT-549、HCC1806、MCF-10A），转染IGF2BP2过表达质粒（OE-IGF2BP2组）、IGF2BP2的siRNA序列（si-IGF2BP2组）、共转染CCNB2野生型报告质粒pmirGLO-CCNB2-WT及空载体OE-NC（WT+NC组）、CCNB2野生型报告质粒pmirGLO-CCNB2-WT及IGF2BP2过表达质粒OE-IGF2BP2（WT+OE组）、CCNB2突变型报告质粒pmirGLO-CCNB2-Mut及空载体OE-NC（Mut+NC组）、CCNB2突变型报告质粒pmirGLO-CCNB2-Mut及IGF2BP2过表达质粒OE-IGF2BP2（Mut+OE组）、IGF2BP2过表达质粒+CCNB2 siRNA序列（OE+si-CCNB2组）的MDA-MB-231细胞，均采用实时定量RT-PCR检测IGF2BP2的mRNA表达水平。将转染空pcDNA3. 1质粒载体命名为OE-NC组（对照组）。采用细胞增殖实验检测各组细胞的吸光度值，Transwell实验检测不同细胞组的迁移和侵袭功能，双荧光素酶报告基因检测CCNB2 mRNA 上m⁶A修饰位点突变前后的荧光素酶活性比值，甲基化RNA免疫共沉淀和RNA免疫共沉淀验证IGF2BP2 与CCNB2之间的结合活性。两组间比较采用t检验，多组间比较采用单因素方差分析，进一步两两比较采用Tukey 法；癌与癌旁组织的mRNA表达量比较采用配对t检验；不同时间点的多组比较采用重复测量方差分析，组间两两比较采用Tukey 法；采用Spearman法分析IGF2BP2与CCNB2 mRNA表达之间的相关性。

结果

癌旁组织中IGF2BP2 mRNA表达水平高于TNBC癌组织（6.51±1.83比1.58±0.59，t=15.620，P<0.001）；有区域淋巴结转移者（19例）的表达高于无区域淋巴结转移者（11例）（7.61±1.16比4.62±1.03，t=7.075，P<0.001）；在Ⅲ~Ⅳ期患者（22例）中的表达高于Ⅰ~Ⅱ期患者（8例）（7.34±1.31比4.24±0.77，t =6.261，P<0. 001）；在正常乳腺上皮MCF-10A细胞和TNBC细胞（MDA-MB-231、MDA-MB-468、BT-549、HCC1806）中的表达分别为1.09±0.11、4.34±0.20、2.25±0.17、1.67±0.16、3.18±0.09，差异有统计学意义（F =281.70，P<0.001）。IGF2BP2 mRNA在OE-IGF2BP2组中的表达高于对照组（3.32±0.18比1.05±0.06，t =23.610，P<0.001）；构建的3个si-IGF2BP2序列（si-IGF2BP2-1#~3#），其IGF2BP2的表达低对照组（0.52±0.04、0.66±0.05、0.33 ±0.04比1.06±0.09，F=81.310，P< 0.001）。对照组、OE-IGF2BP2组、si-IGF2BP2组细胞的吸光度值比较，差异有统计学意义（组间比较：F=300.00，P<0.001；时间点比较：F=947.20，P <0.001；交互作用：F=45.390，P<0. 001）；3组迁移细胞数分别为186.30±8.08、254.70±6.03、122.70±8.62，组间比较差异有统计学意义（F=222.80，P<0.001）；3组的侵袭细胞数分别为152.70±11.02、222.70±9.45、81.67±7.02，组间比较差异有统计学意义（F=172.10，P<0.000 1）；3组的CCNB2 mRNA表达量分别为1.05±0.07、2.95±0.07、0.62± 0.04，组间比较差异有统计学意义（F=1 193.000，P<0.001）；3组CCNB2 mRNA稳定性比较差异有统计学意义（组间比较：F=72.430，P<0.001；时间点比较：F=511. 30，P<0.001；交互作用：F=23.930，P<0. 001）。TNBC组织中CCNB2的mRNA表达水平高于癌旁组织（5.03±1.62比1.42±0.49，t=13.140，P<0.001），且CCNB2 mRNA表达与IGF2BP2 mRNA表达呈正相关（r=0.704 3，P<0.001）。WT+OE组细胞的荧光素酶活性比值低于对照组（5.33±0.79比12.33±1.11，t =8.895，P<0.001）。抗m⁶A组中甲基化修饰的CCNB2富集程度显著增加（t=15.94，P<0.001），抗IGF2BP2组中CCNB2富集程度显著增加（t=19.610，P<0.001）。对照组、OE+si-NC组、OE+si-CCNB2组细胞的A值比较，差异具有统计学意义（组间比较：F=542.500，P<0.001；时间点比较：F=867.400，P<0.001；交互作用：F=47.570，P<0.001）；这3组细胞的迁移细胞数分别为144.00±4.58、258.00±5.29、175.00±8.89，差异有统计学意义（F=244.300，P<0.001）；3组侵袭细胞数分别为113.30±11.50、214.70±7.37、152.70±9.71，差异有统计学意义（F=83.590，P<0.001）。

结论

IGF2BP2通过m⁶A依赖方式增强CCNB2 mRNA稳定性，促进TNBC细胞增殖、迁移和侵袭。

关键词: 乳腺肿瘤, 三阴性乳腺癌, RNA结合蛋白, 肿瘤基因表达调控

Objectives

To investigate the role and mechanism of the m6A-dependent IGF2BP2/CCNB2 axis in the progression of triple negative breast cancer (TNBC).

Methods

Tumor and adjacent normal tissue specimens were collected from 30 TNBC patients who underwent surgery in the Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Army Medical University between May 2020 and April 2023. Human normal breast epithelial cell line MCF-10A and TNBC cell lines (MDA-MB-231, MDA-MB-468, BT-549, HCC1806, and MCF-10A) were used. Real-time quantitative RT-PCR was used to measure IGF2BP2 mRNA between tumor tissue and adjacent normal tissue, and among different cell lines. The MDA-MB-231 cells were transfected with the IGF2BP2 overexpression plasmid (OE-IGF2BP2 group), IGF2BP2 siRNA sequence (si-IGF2BP2 group), wild-type CCNB2 reporter plasmid pmirGLO-CCNB2-WT and empty vector OE-NC (WT+NC group), wild-type CCNB2 reporter plasmid pmirGLO-CCNB2-WT and IGF2BP2 overexpression plasmid OE-IGF2BP2 (WT+OE group), mutant-type CCNB2 reporter plasmid pmirGLO-CCNB2-Mut and empty vector OE-NC (Mut+NC group), mutant-type CCNB2 reporter plasmid pmirGLO-CCNB2-Mut and IGF2BP2 overexpression plasmid OE-IGF2BP2 (Mut+OE group), IGF2BP2 overexpression plasmid and CCNB2 siRNA (OE+si-CCNB2 group). Real-time quantitative RT-PCR was used to measure IGF2BP2 mRNA expression in each group. Cell proliferation assays were used to measure optical density; Transwell assays were used to assess cell migration and invasion; dual-luciferase reporter were used to detect the ratio of luciferase activity of wild-type and mutant m6A sites on CCNB2 mRNA. The methylated RNA immunoprecipitation (MeRIP) and RNA immunoprecipitation (RIP) were used to validate the binding activity between IGF2BP2 and CCNB2. The continuous data were compared between two groups using t tests; among multiple groups using one-way ANOVA and pairwise comparisons by Tukey's test. The mRNA expression levels of two factors between tumor tissue and adjacent tissues were compared by paired t test; multiple-group comparisons at different time points were analyzed by repeated measures analysis of variance with pairwise comparison by Tukey's test. The correlation between IGF2BP2 and CCNB2 mRNA expression was analyzed by Spearman method.

Results

IGF2BP2 mRNA expression in adjacent normal tissue was significantly higher than that in TNBC tumor tissue (1.58±0.59 vs 6.51±1.83, t=15.620, P<0.001). The IGF2BP2 mRNA expression in patients with regional lymph node metastasis (n=19) was significantly higher than that in those without (n=11) (4.62±1.03 vs 7.61±1.16, t=7.075, P<0.001). The IGF2BP2 mRNA expression in stage Ⅲ–Ⅳ breast cancer patients (n=22) was significantly higher than that in stage Ⅰ–Ⅱ breast cancer patients (n=8) (7.34±1.31 vs 4.24±0.77, t=6.261, P<0.001). The IGF2BP2 mRNA expression in MCF-10A and TNBC cell lines (MDA-MB-231, MDA-MB-468, BT-549, HCC1806) was 1.09±0.11, 4.34±0.20, 2.25±0.17, 1.67±0.16, and 3.18±0.09, respectively, indicating a significant difference (F=281.70, P<0.001). The IGF2BP2 mRNA expression was significantly higher in OE-IGF2BP2 group than in control group (3.32±0.18 vs 1.05±0.06, t=23.610, P<0.001); lower in si-IGF2BP2 group than in control group (0.33±0.04 vs 0.66±0.05, F=81.310, P<0.001). The optical density values in control, OE-IGF2BP2 and si-IGF2BP2 groups showed a significant difference (between groups: F=300.00, P<0.001; time points: F=947.20, P<0.001; interaction: F=45.390, P<0.001); migration cell counts were 186.30±8.08, 254.70±6.03, 122.70±8.62, respectively, indicating a significant difference (F=222.80, P<0.001); invasion cell counts were 152.70±11.02, 222.70±9.45, 81.67±7.02, respectively, indicating a significant difference (F=172.10, P<0.0001); CCNB2 mRNA expression was 1.05±0.07, 2.95±0.07, 0.62±0.04, respectively, indicating a significant difference (F=1193, P<0.001); CCNB2 mRNA stability differed significantly among groups (between groups: F=72.430, P<0.001; time points: F=511.30, P<0.001; interaction: F=23.930, P<0.001). CCNB2 mRNA expression in TNBC tissue was significantly higher than that in adjacent tissue (5.03±1.62 vs 1.42±0.49, t=13.140, P<0.001), and CCNB2 mRNA expression was positively correlated with IGF2BP2 mRNA (r=0.7043, P<0.001). The ratio of luciferase activity in WT+OE group were significantly higher than that in control group (12.33±1.11 vs 5.33±0.79, t=8.895, P<0.001). The methylated CCNB2 enrichment was significantly increased in the anti-m6A group (t=15.94, P<0.001), and CCNB2 enrichment was also elevated in the anti-IGF2BP2 group (t=19.61, P<0.001). The optical density values in control, OE+si-NC, and OE+si-CCNB2 groups showed a significant difference (between groups: F=122.40, P<0.001; time points: F=2279.000, P<0.001; interaction: F=24.530, P<0.001); migration cell counts were 144.00±4.58, 258.00±5.29, and 175.00±8.89, respectively, indicating a significant difference (F=244.300, P<0.001); invasion cell counts were 113.30±11.50, 214.70±7.37, and 152.70±9.71, respectively, indicating a significant difference (F=83.590, P<0.001).

Conclusion

IGF2BP2 enhances the stability of CCNB2 mRNA in an m6A-dependent manner, thus promoting proliferation, migration, and invasion of TNBC cells.

Key words: Breast neoplasms, Triple negative breast cancer, RNA-binding proteins, Gene expression regulation，neoplastic

表1 实时荧光定量PCR的基因引物序列

引物名称	引物序列
IGF2BP2	F： 5’-CTACGCCTTCGTGGACTACC-3’
	R： 5’-CATCCAACACCTCCCACTG-3’
CCNB2	F： 5’-CTCGGAGAGCAGTCCTAACG-3’
	R： 5’-CAAATCACTGGACACCGTCG-3’
GAPDH	F： 5’-TGACTTCAACAGCGACACCCA-3’
	R： 5’-CACCCTGTTGCTGTAGCCAAA-3’

表1 实时荧光定量PCR的基因引物序列

引物名称	引物序列
IGF2BP2	F： 5’-CTACGCCTTCGTGGACTACC-3’
	R： 5’-CATCCAACACCTCCCACTG-3’
CCNB2	F： 5’-CTCGGAGAGCAGTCCTAACG-3’
	R： 5’-CAAATCACTGGACACCGTCG-3’
GAPDH	F： 5’-TGACTTCAACAGCGACACCCA-3’
	R： 5’-CACCCTGTTGCTGTAGCCAAA-3’

表2 IGF2BP2过表达和敲除的MDA-MB-231细胞吸光度值比较

组别	0 h	24 h	48 h	72 h	96 h
NC组	0.27±0.04	0.53±0.04	1.08±0.09	1.53±0.03	1.81±0.02
OE-IGF2BP2组	0.27±0.06	0.58±0.03	1.58±0.05^a	1.89±0.07^a	2.23±0.10^a
si-IGF2BP2组	0.27±0.09	0.49±0.02^b	0.64±0.05^ab	1.03±0.08^ab	1.32±0.06^ab
F值	0.006	5.672	138.716	133.382	128.761
P值	0.994	0.041	<0.001	<0.001	<0.001

表2 IGF2BP2过表达和敲除的MDA-MB-231细胞吸光度值比较

组别	0 h	24 h	48 h	72 h	96 h
NC组	0.27±0.04	0.53±0.04	1.08±0.09	1.53±0.03	1.81±0.02
OE-IGF2BP2组	0.27±0.06	0.58±0.03	1.58±0.05^a	1.89±0.07^a	2.23±0.10^a
si-IGF2BP2组	0.27±0.09	0.49±0.02^b	0.64±0.05^ab	1.03±0.08^ab	1.32±0.06^ab
F值	0.006	5.672	138.716	133.382	128.761
P值	0.994	0.041	<0.001	<0.001	<0.001

图1 MDA-MB-231细胞Transwell迁移和侵袭实验结果（结晶紫染色 ×100）　a、b、c图分别为NC、OE-IGF2BP2、si-IGF2BP2组迁移实验结果；d、e、f图分别为NC、OE-IGF2BP2、si-IGF2BP2组侵袭实验结果注： IGF2BP2为胰岛素样生长因子2 mRNA结合蛋白2；NC组为共转染空载体OE-NC及阴性对照siRNA的MDA-MB-231细胞对照组；OE-IGF2BP2组为转染IGF2BP2过表达质粒的MDA-MB-231细胞；si-IGF2BP2组为转染IGF2BP2 siRNA的MDA-MB-231细胞

图2 CCNB2 mRNA表达与IGF2BP2 mRNA表达的相关性分析结果注：IGF2BP2为胰岛素样生长因子2 mRNA结合蛋白2；CCNB2为细胞周期蛋白B2；r =0.704 3，P<0.001

表3 IGF2BP2过表达和敲除的MDA-MB-231细胞CCNB2相对 mRNA水平比较

组别	0 h	3 h	6 h	9 h	12 h
NC组	1.09±0.35	0.74±0.04	0.67±0.02	0.57±0.05	0.40±0.04
OE-IGF2BP2组	1.03±0.07	0.92±0.03^a	0.81±0.02^a	0.72±0.04^a	0.66±0.03^a
si-IGF2BP2组	1.06±0.06	0.62±0.03^ab	0.47±0.05^ab	0.37±0.03^ab	0.23±0.03^ab
F值	0.807	70.391	81.295	56.086	137.187
P值	0.489	<0.001	<0.001	<0.001	<0.001

表3 IGF2BP2过表达和敲除的MDA-MB-231细胞CCNB2相对 mRNA水平比较

组别	0 h	3 h	6 h	9 h	12 h
NC组	1.09±0.35	0.74±0.04	0.67±0.02	0.57±0.05	0.40±0.04
OE-IGF2BP2组	1.03±0.07	0.92±0.03^a	0.81±0.02^a	0.72±0.04^a	0.66±0.03^a
si-IGF2BP2组	1.06±0.06	0.62±0.03^ab	0.47±0.05^ab	0.37±0.03^ab	0.23±0.03^ab
F值	0.807	70.391	81.295	56.086	137.187
P值	0.489	<0.001	<0.001	<0.001	<0.001

表4 IGF2BP2过表达的MDA-MB-231细胞敲除CCNB2表达后吸光度值比较

组别	0 h	24 h	48 h	72 h	96 h
NC组	0.19±0.01	0.55±0.03	1.12±0.09	1.40±0.03	1.65±0.08
OE+si-NC组	0.21±0.02	0.72±0.04^a	1.66±0.04^a	1.89±0.03^a	2.14±0.08^a
OE+si-CCNB2组	0.20±0.02	0.52±0.02^b	1.25±0.07^b	1.51±0.01^ab	1.73±0.04^b
F值	1.526	35.161	42.699	351.255	50.143
P值	0.291	<0.001	<0.001	<0.001	<0.001

表4 IGF2BP2过表达的MDA-MB-231细胞敲除CCNB2表达后吸光度值比较

组别	0 h	24 h	48 h	72 h	96 h
NC组	0.19±0.01	0.55±0.03	1.12±0.09	1.40±0.03	1.65±0.08
OE+si-NC组	0.21±0.02	0.72±0.04^a	1.66±0.04^a	1.89±0.03^a	2.14±0.08^a
OE+si-CCNB2组	0.20±0.02	0.52±0.02^b	1.25±0.07^b	1.51±0.01^ab	1.73±0.04^b
F值	1.526	35.161	42.699	351.255	50.143
P值	0.291	<0.001	<0.001	<0.001	<0.001

图3 MDA-MB-231细胞Transwell迁移和侵袭实验结果（结晶紫染色 ×100）　a、b、c图分别为NC、OE+si-NC、OE+si-CCNB2组迁移实验结果；d、e、f图分别为NC、OE+si-NC、OE+si-CCNB2组侵袭实验结果注： IGF2BP2为胰岛素样生长因子2 mRNA结合蛋白2；CCNB2为细胞周期蛋白B2；NC组为共转染空载体OE-NC及阴性对照siRNA的MDA-MB-231细胞对照组；OE+si-NC组为共转染IGF2BP2过表达质粒的MDA-MB-231细胞和阴性对照siRNA si-NC；OE+si-CCNB2组为共转染IGF2BP2 过表达质粒和CCNB2 siRNA的MDA-MB-231细胞

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Mechanism of IGF2BP2/CCNB2 axis promoting the progression of triple negative breast cancer

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Mechanism of IGF2BP2/CCNB2 axis promoting the progression of triple negative breast cancer