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Quercetin Inhibits Adenomyosis by Attenuating Cell Proliferation, Migration and Invasion of Ectopic Endometrial Stromal Cells
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2020-09-21 , DOI: 10.2147/dddt.s265066 Wenbin Xu 1 , Yizuo Song 1 , Kehan Li 1 , Biyun Zhang 2 , Xueqiong Zhu 1
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2020-09-21 , DOI: 10.2147/dddt.s265066 Wenbin Xu 1 , Yizuo Song 1 , Kehan Li 1 , Biyun Zhang 2 , Xueqiong Zhu 1
Affiliation
Purpose: To evaluate the effects of quercetin on proliferation, invasion and migration of endometrial stromal cells (ESCs) from adenomyosis patients.
Methods: Primary ectopic ESCs (EESCs) and eutopic ESCs (EuESCs) were obtained and purified from patients undergoing total hysterectomy for adenomyosis and identified by immunocytochemistry staining. The cytotoxicity and inhibition rate were determined by CCK-8 assay to obtain the IC50 value. Cell proliferative, migratory, and invasive abilities were detected by BrdU, wound scratch, transwell assays, respectively. Western blot analysis was employed to explore the effects of quercetin on the expression of MMP-2, MMP-9, Ezrin and Fascin proteins in cells.
Results: Both EESCs and EuESCs were characterized with strongly positive staining for vimentin and almost negative for cytokeratin. Quercetin inhibited the viability of EESCs and EuESCs in a dose- and time-dependent manner, with an IC50 = 33.00 μM for EuESCs and IC50 = 74.88 μM for EESCs at 72 h. Thus, the final concentrations and action time of quercetin in EuESCs (0, 20, 40, and 80 μM for 72 h) and EESCs (0, 40, 80, and 160 μM for 72 h) were selected. BrdU assay showed that quercetin dose-dependently suppressed the proliferation of EESCs and EuESCs, while the inhibition rate in EESCs was higher. Similarly, administration of quercetin in EESCs and EuESCs significantly decreased the motility and invasiveness in a dose-dependent fashion, with stronger inhibitory effects on EESCs. Finally, Western blot analysis demonstrated that invasion- and migration-related proteins (MMP-2, MMP-9, Erzin, and Fascin) were significantly downregulated with the quercetin concentration increasing. Moreover, the decreased level of these proteins in EESCs under quercetin exposure was greater than that in EuESCs.
Conclusion: Quercetin can inhibit the proliferation of EESCs in adenomyosis and reduce their mobility and invasiveness. These inhibitory effects may be related to the downregulation of MMP-2, MMP-9, Fascin, and Erzin proteins.
Keywords: quercetin, adenomyosis, proliferation, migration, invasion
中文翻译：
槲皮素通过减弱异位子宫内膜基质细胞的细胞增殖、迁移和侵袭来抑制子宫腺肌病
目的：评价槲皮素对子宫内膜间质细胞（ESCs）增殖、侵袭和迁移的影响。
方法：原发性异位 ESCs (EESCs) 和在位 ESCs (EuESCs) 从因子宫腺肌病接受全子宫切除术的患者中获得和纯化，并通过免疫细胞化学染色鉴定。用CCK-8法测定细胞毒性和抑制率，得到IC 50值。BrdU、伤口划痕、transwell 检测分别检测到细胞增殖、迁移和侵袭能力。采用Western blot分析槲皮素对细胞内MMP-2、MMP-9、Ezrin和Fascin蛋白表达的影响。
结果：EESCs 和 EuESCs 的特点是波形蛋白染色呈强阳性，而细胞角蛋白染色几乎呈阴性。槲皮素以剂量和时间依赖性方式抑制 EESCs 和 EuESCs 的活力，对 EuESCs 和 IC 50 的 IC 50 = 33.00 μMEESC 在 72 小时时 = 74.88 μM。因此，选择了槲皮素在 EuESCs（0、20、40 和 80 μM，72 小时）和 EESCs（0、40、80 和 160 μM，72 小时）中的最终浓度和作用时间。BrdU测定显示槲皮素剂量依赖性地抑制EESCs和EuESCs的增殖，而对EESCs的抑制率更高。同样，在 EESCs 和 EuESCs 中施用槲皮素以剂量依赖性方式显着降低运动性和侵袭性，对 EESCs 具有更强的抑制作用。最后，蛋白质印迹分析表明，随着槲皮素浓度的增加，侵袭和迁移相关蛋白（MMP-2、MMP-9、Erzin 和 Fascin）显着下调。此外，在槲皮素暴露下，EESCs 中这些蛋白质的水平下降幅度大于 EuESCs。
结论：槲皮素能抑制子宫腺肌症中EESCs的增殖，降低其活动性和侵袭性。这些抑制作用可能与 MMP-2、MMP-9、Fascin 和 Erzin 蛋白的下调有关。
关键词：槲皮素，子宫腺肌病，增殖，迁移，侵袭
更新日期：2020-09-21
Methods: Primary ectopic ESCs (EESCs) and eutopic ESCs (EuESCs) were obtained and purified from patients undergoing total hysterectomy for adenomyosis and identified by immunocytochemistry staining. The cytotoxicity and inhibition rate were determined by CCK-8 assay to obtain the IC50 value. Cell proliferative, migratory, and invasive abilities were detected by BrdU, wound scratch, transwell assays, respectively. Western blot analysis was employed to explore the effects of quercetin on the expression of MMP-2, MMP-9, Ezrin and Fascin proteins in cells.
Results: Both EESCs and EuESCs were characterized with strongly positive staining for vimentin and almost negative for cytokeratin. Quercetin inhibited the viability of EESCs and EuESCs in a dose- and time-dependent manner, with an IC50 = 33.00 μM for EuESCs and IC50 = 74.88 μM for EESCs at 72 h. Thus, the final concentrations and action time of quercetin in EuESCs (0, 20, 40, and 80 μM for 72 h) and EESCs (0, 40, 80, and 160 μM for 72 h) were selected. BrdU assay showed that quercetin dose-dependently suppressed the proliferation of EESCs and EuESCs, while the inhibition rate in EESCs was higher. Similarly, administration of quercetin in EESCs and EuESCs significantly decreased the motility and invasiveness in a dose-dependent fashion, with stronger inhibitory effects on EESCs. Finally, Western blot analysis demonstrated that invasion- and migration-related proteins (MMP-2, MMP-9, Erzin, and Fascin) were significantly downregulated with the quercetin concentration increasing. Moreover, the decreased level of these proteins in EESCs under quercetin exposure was greater than that in EuESCs.
Conclusion: Quercetin can inhibit the proliferation of EESCs in adenomyosis and reduce their mobility and invasiveness. These inhibitory effects may be related to the downregulation of MMP-2, MMP-9, Fascin, and Erzin proteins.
Keywords: quercetin, adenomyosis, proliferation, migration, invasion
中文翻译：
槲皮素通过减弱异位子宫内膜基质细胞的细胞增殖、迁移和侵袭来抑制子宫腺肌病
目的：评价槲皮素对子宫内膜间质细胞（ESCs）增殖、侵袭和迁移的影响。
方法：原发性异位 ESCs (EESCs) 和在位 ESCs (EuESCs) 从因子宫腺肌病接受全子宫切除术的患者中获得和纯化，并通过免疫细胞化学染色鉴定。用CCK-8法测定细胞毒性和抑制率，得到IC 50值。BrdU、伤口划痕、transwell 检测分别检测到细胞增殖、迁移和侵袭能力。采用Western blot分析槲皮素对细胞内MMP-2、MMP-9、Ezrin和Fascin蛋白表达的影响。
结果：EESCs 和 EuESCs 的特点是波形蛋白染色呈强阳性，而细胞角蛋白染色几乎呈阴性。槲皮素以剂量和时间依赖性方式抑制 EESCs 和 EuESCs 的活力，对 EuESCs 和 IC 50 的 IC 50 = 33.00 μMEESC 在 72 小时时 = 74.88 μM。因此，选择了槲皮素在 EuESCs（0、20、40 和 80 μM，72 小时）和 EESCs（0、40、80 和 160 μM，72 小时）中的最终浓度和作用时间。BrdU测定显示槲皮素剂量依赖性地抑制EESCs和EuESCs的增殖，而对EESCs的抑制率更高。同样，在 EESCs 和 EuESCs 中施用槲皮素以剂量依赖性方式显着降低运动性和侵袭性，对 EESCs 具有更强的抑制作用。最后，蛋白质印迹分析表明，随着槲皮素浓度的增加，侵袭和迁移相关蛋白（MMP-2、MMP-9、Erzin 和 Fascin）显着下调。此外，在槲皮素暴露下，EESCs 中这些蛋白质的水平下降幅度大于 EuESCs。
结论：槲皮素能抑制子宫腺肌症中EESCs的增殖，降低其活动性和侵袭性。这些抑制作用可能与 MMP-2、MMP-9、Fascin 和 Erzin 蛋白的下调有关。
关键词：槲皮素，子宫腺肌病，增殖，迁移，侵袭
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