丝氨酸蛋白酶抑制剂E1过表达通过诱导M2型巨噬细胞极化促进三阴性乳腺癌细胞增殖与紫杉醇耐药

doi:10.12122/j.issn.1673-4254.2025.12.03

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (12): 2551-2560.doi: 10.12122/j.issn.1673-4254.2025.12.03

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丝氨酸蛋白酶抑制剂E1过表达通过诱导M2型巨噬细胞极化促进三阴性乳腺癌细胞增殖与紫杉醇耐药

张芡¹(), 刘博文¹, 雷丽¹, 王晔¹, 张馨月¹, 毛樟坤¹, 唐鹏², 张金梅², 杨佳宜¹, 彭彦茜³, 刘泽⁴()

^1.湘南学院，附属医院（临床学院），湖南郴州 423000
^2.湘南学院，药学院，湖南郴州 423000
^3.湘南学院，公共卫生学院，湖南郴州 423000
^4.湘南学院，护理学院，湖南郴州 423000

收稿日期:2025-05-01 出版日期:2025-12-20 发布日期:2025-12-22
通讯作者: 刘泽 E-mail:zhangqian@xnu.edu.cn;582842343@qq.com
作者简介:张芡，硕士，副教授，E-mail: zhangqian@xnu.edu.cn
基金资助:
湖南省自然科学基金区域联合基金项目(2023JJ50412);湖南省教育厅科学研究重点项目(23A0596);2024年湖南省大学生创新训练计划项目(4861)

SERPINE1 overexpression promotes proliferation and paclitaxel resistance of triple-negative breast cancer cells by inducing M2 macrophage polarization

Qian ZHANG¹(), Bowen LIU¹, Li LEI¹, Ye WANG¹, Xinyue ZHANG¹, Zhangkun MAO¹, Peng TANG², Jinmei ZHANG², Jiayi YANG¹, Yanxi PENG³, Ze LIU⁴()

^1.Affiliated Hospital (School of Clinical Medicine), Xiangnan University, Chenzhou 423000, China
^2.School of Pharmacology, Xiangnan University, Chenzhou 423000, China
^3.School of Public Health, Xiangnan University, Chenzhou 423000, China
^4.School of Nursing, Xiangnan University, Chenzhou 423000, China

Received:2025-05-01 Online:2025-12-20 Published:2025-12-22
Contact: Ze LIU E-mail:zhangqian@xnu.edu.cn;582842343@qq.com

摘要/Abstract

摘要：

目的探讨丝氨酸蛋白酶抑制剂E1（SERPINE1）对三阴性乳腺癌细胞肿瘤免疫微环境的影响及其与紫杉醇（PTX）耐药性的关系。方法采用0~40 µmol/L的PTX处理三阴性乳腺癌细胞系MDA-MB-231，并利用CCK-8法测定PTX对MDA-MB-231细胞的半数抑制浓度（IC₅₀值）。通过低剂量逐步递增的方法，在体外建立PTX耐药模型（MDA-MB-231/PTX）。分别将SERPINE1过表达质粒或SERPINE1 siRNA转染至野生型和耐药型MDA-MB-231细胞株，以实现SERPINE1的过表达或敲低。采用Western blotting检测各组细胞中SERPINE1的表达水平，以评估转染效率。利用Hoechst 33258染色法评估细胞凋亡情况，并通过Western blotting测定凋亡相关的活化天冬氨酸特异性半胱氨酸蛋白酶（cleaved-caspase 3）的表达水平。采用EdU和CCK-8法检测细胞增殖活力。将各组乳腺癌细胞与巨噬细胞共培养后，利用流式细胞术和Western blotting检测巨噬细胞的M1、M2极化水平，并计算M1/M2值。进一步构建裸鼠皮下移植瘤模型，通过监测肿瘤生长及免疫组化染色验证其体内作用。结果 SERPINE1的过表达抑制MDA-MB-231细胞的凋亡并促进细胞增殖（P<0.01），而敲低SERPINE1则促进MDA-MB-231/PTX细胞的凋亡并抑制细胞增殖（P<0.01）。此外，SERPINE1高表达的乳腺癌细胞有助于巨噬细胞向M2型极化、抑制M1极化、降低M1/M2比值（P<0.01）。体内移植瘤实验同样证实，过表达SERPINE1促进肿瘤生长（P<0.01）。结论在MDA-MB-231三阴性乳腺癌细胞中，SERPINE1的过表达促进细胞增殖、抑制细胞凋亡，并增强对PTX的耐药性。SERPINE1参与调控乳腺癌微环境中巨噬细胞的极化状态，促进M2型巨噬细胞的极化。

关键词: 三阴性乳腺癌, 丝氨酸蛋白酶抑制剂E1, 紫杉醇耐药, 肿瘤免疫微环境, M2型巨噬细胞极化

Abstract:

Objective To investigate the regulatory effect of Serpin Family E Member 1 (SERPINE1) on immune microenvironment and paclitaxel (PTX) resistance of triple-negative breast cancer (TNBC) cells. Methods CCK-8 assay was used to determine the half-maximal inhibitory concentration of PTX in TNBC cell line MDA-MB-231. In wild-type MDA-MB-231 cells and a PTX-resistant MDA-MB-231 cell line (MDA-MB-231/PTX) established by stepwise increasing low-dose PTX treatment, the effects of Western blot-verified transfection with SERPINE1 overexpression plasmids or SERPINE1 siRNAs on cell apoptosis were evaluated using Hoechst 33258 staining and by detecting expression levels of cleaved caspase-3 using Western blotting. The changes in proliferation of the transfected cells were assessed using EdU and CCK-8 assays. The breast cancer cells with different treatments were co-cultured with macrophages, and M1 and M2 polarization of the macrophages were analyzed with flow cytometry and Western blotting. In nude mouse models bearing subcutaneous breast cancer cell xenografts, the effects of SERPINE1 overexpression and knockdown in the engrafted cells on tumor growth and PTX resistance were evaluated. Results SERPINE1 overexpression significantly inhibited apoptosis and promoted proliferation of MDA-MB-231 cells, and SERPINE1 knockdown obviously promoted apoptosis and inhibited proliferation of MDA-MB-231/PTX cells. The macrophages co-cultured with SERPINE1-overexpressing breast cancer cells showed enhanced M2 polarization and suppressed M1 polarization with a lowered M1/M2 ratio. In the tumor-bearing nude mouse models, SERPINE1 overexpression in the engrafted cells resulted in significantly accelerated tumor growth. Conclusion In MDA-MB-231 cells, SERPINE1 overexpression promotes cell proliferation, inhibits apoptosis, and enhances PTX resistance. SERPINE1 plays a regulatory role in macrophage polarization in the immune microenvironment of breast cancer, and its high expression promotes M2 polarization of the macrophages.

Key words: triple-negative breast cancer, serpin family E member 1, paclitaxel resistance, tumor immune microenvironment, M2 macrophage polarization

张芡, 刘博文, 雷丽, 王晔, 张馨月, 毛樟坤, 唐鹏, 张金梅, 杨佳宜, 彭彦茜, 刘泽. 丝氨酸蛋白酶抑制剂E1过表达通过诱导M2型巨噬细胞极化促进三阴性乳腺癌细胞增殖与紫杉醇耐药[J]. 南方医科大学学报, 2025, 45(12): 2551-2560.

Qian ZHANG, Bowen LIU, Li LEI, Ye WANG, Xinyue ZHANG, Zhangkun MAO, Peng TANG, Jinmei ZHANG, Jiayi YANG, Yanxi PENG, Ze LIU. SERPINE1 overexpression promotes proliferation and paclitaxel resistance of triple-negative breast cancer cells by inducing M2 macrophage polarization[J]. Journal of Southern Medical University, 2025, 45(12): 2551-2560.

图/表 8

图1 MDA-MB-231细胞和MDA-MB-231/PTX细胞分别进行SERPINE1过表达和敲低干预

Fig.1 SERPINE1 overexpression in MDA-MB-231 cells and SERPINE1 knockdown in MDA-MB-231/PTX cells. A, B: Western blotting for detecting SERPINE1 protein expression in MDA-MB-231 cells transfected with pcDNA4.0-SERPINE1 and vector plasmid (**P<0.01 vs EV group, n=3); C, D: Western blotting for detecting SERPINE1 protein expression in MDA-MB-231/PTX cells transfected with SERPINE1-siRNA and NC-siRNA. GAPDH was used as the loading control (*P<0.05 vs NC group, n=3).

图2 SERPINE1对三阴性乳腺癌细胞增殖活力影响

Fig.2 Proliferative activity of MDA-MB-231 cells with SERPINE1 overexpression and MDA-MB-231/PTX cells with SERPINE1 knockdown. A, B: Results of CCK-8 assay of MDA-MB-231 cells (A) transfected with pcDNA4.0-SERPINE1 or the vector plasmid and MDA-MB-231/PTX cells (B) transfected with SERPINE1-siRNA or NC-siRNA (**P<0.01 vs EV group or NC group). C, D: EdU staining of MDA-MB-231 cells with SERPINE1 overexpression and MDA-MB-231/PTX cells with SERPINE1 knockdown (scale bar=50 μm).

图3 SERPINE1对三阴性乳腺癌细胞凋亡影响

Fig.3 Changes in apoptosis of MDA-MB-231 cells with SERPINE1 overexpression and MDA-MB-231/PTX cells with SERPINE1 knockdown. A, B: DNA damage detected by Hoechst staining in MDA-MB-231 cells with SERPINE1 overexpression and in MDA-MB-231/PTX cells with SERPINE1 knockdown (scale bar=50 μm). C: Western blotting for detecting protein levels of cleaved caspase-3 in MDA-MB-231 cells transfected with pcDNA4.0-SERPINE1 versus the vector plasmid (**P<0.01 vs EV group). D: Western blotting for detecting protein levels of cleaved caspase-3 in MDA-MB-231/PTX cells transfected with SERPINE1-siRNA versus NC-siRNA (***P<0.001 vs NC group, n=3).

图4 SERPINE1对三阴性乳腺癌细胞PTX耐药性的影响

Fig.4 Changes in paclitaxel resistance of MDA-MB-231 cells with SERPINE1 overexpression and MDA-MB-231/PTX cells with SERPINE1 knockdown. A: CCK-8 assay for determining IC50 value of paclitaxel in MDA-MB-231 cells transfected with pcDNA4.0-SERPINE1 versus the vector plasmid (**P<0.01 vs EV group). B: CCK-8 assay for determining the IC50 value of paclitaxel in MDA-MB-231/PTX cells transfected with SERPINE1-siRNA versus NC-siRNA (**P<0.01 vs NC group, n=3).

图5 三阴性乳腺癌细胞中SERPINE1对巨噬细胞M2极化影响

Fig.5 Effect of SERPINE1 overexpression in MDA-MB-231 cells and SERPINE1 knockdown in MDA-MB-231/PTX cells on M2 polarization of the co-cultured macrophages. A, B: Flow cytometry for analyzing the proportion of CD163+ macrophages co-cultured with SERPINE1-overexpressing MDA-MB-231 cells (**P<0.01 vs EV group). C, D: Flow cytometry for analyzing the proportion of CD163+ macrophages co-cultured with MDA-MB-231/PTX cells with SERPINE1 knockdown (*P<0.05 vs NC group). E, F: Western blotting for detecting the protein expression of YM1 and Arg-1 in the macrophages from the microenvironment of MDA-MB-231 cells with or without SERPINE1 overexpression (**P<0.01 vs EV group). G, H: Western blotting for detecting the protein expression of YM1 and Arg-1 in macrophages from the microenvironment of MDA-MB-231/PTX cells with or without SERPINE1 knockdown (**P<0.01 vs NC group, n=3).

图6 三阴性乳腺癌细胞中SERPINE1对巨噬细胞M1极化影响

Fig.6 M1 polarization of the macrophages co-cultured with MDA-MB-231 cells with SERPINE1 overexpression or MDA-MB-231/PTX cells with SERPINE1 knockdown. A, B: Flow cytometry for analyzing the proportion of CD86+ macrophages co-cultured with MDA-MB-231 cells with SERPINE1 overexpression (*P<0.05 vs EV group). C, D: Flow cytometry for analyzing the proportion of CD86+ macrophages co-cultured with MDA-MB-231/PTX cells with SERPINE1 knockdown (**P<0.01 vs NC group). E, F: Western blotting for detecting the protein expression of iNOS in macrophages from the microenvironment of MDA-MB-231 cells with or without SERPINE1 overexpression (**P<0.01 vs EV group). G, H: Western blotting for detecting the protein expression of iNOS in macrophages from the microenvironment of MDA-MB-231/PTX cells with or without SERPINE1 knockdown (**P<0.01 vs NC group, n=3).

图7 三阴性乳腺癌细胞中SERPINE1对巨噬细胞M1/M2比值影响

Fig.7 M1/M2 ratio of the macrophages co-cultured with MDA-MB-231 cells with SERPINE1 overexpression (A; **P<0.01 vs EV group) and MDA-MB-231/PTX cells with SERPINE1 knockdown (B; **P<0.01 vs blank group, n=3).

图8 SERPINE1在体内对三阴性乳腺癌生长的影响及对巨噬细胞极化的调控

Fig.8 Regulatory effect of SERPINE1 expression level on growth of triple-negative breast cancer xenografts and macrophage polarization in nude mice. A: Appearance of the tumor-bearing nude mice and the dissected tumors. B: Tumor growth curves over time in each group. C: Protein expression level of SERPINE1 in the xenograft tumor tissues from each group. D: HE staining of xenograft tumor tissues. E: Immunohistochemistry for the M2 macrophage marker Arg-1 in xenograft tumor tissues. F: Immunohistochemistry for the M1 macrophage marker iNOS in xenograft tumor tissues (scale bar=100 μm). *P<0.05, **P<0.01, ***P<0.001 vs NC group. n=6.

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丝氨酸蛋白酶抑制剂E1过表达通过诱导M2型巨噬细胞极化促进三阴性乳腺癌细胞增殖与紫杉醇耐药

SERPINE1 overexpression promotes proliferation and paclitaxel resistance of triple-negative breast cancer cells by inducing M2 macrophage polarization

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