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. 2023 Aug 20;43(8):1315-1321.
doi: 10.12122/j.issn.1673-4254.2023.08.07.

[Guizhi Fuling Capsule inhibits migration and induces apoptosis of human ovarian cancer cells by regulating the NF-κB signaling pathway]

[Article in Chinese]
X Guo  1 , L Chen  1   2 , Q Lü  3 , R DU  1   2 , Q Luo  1 , Y Zhang  1 , H Bian  1   2 , L Han  1   2
Affiliations

[Guizhi Fuling Capsule inhibits migration and induces apoptosis of human ovarian cancer cells by regulating the NF-κB signaling pathway]

[Article in Chinese]
X Guo et al. Nan Fang Yi Ke Da Xue Xue Bao. .

Abstract
in English, Chinese

Objective: To study the inhibitory effect of Guizhi Fuling Capsule (GFC) on migration of human ovarian cancer cells and explore the possible mechanism.

Methods: Sixty Wistar rats were randomized into 4 groups for daily gavage of saline or 4, 8, or 16 g/kg GFC suspension for 5 days to prepare blank and low-, medium- and high-dose GFC-medicated sera. Cisplatinresistant ovarian cancer SKOV3/DDP cells were treated with these sera with nuclear factor-κB (NF-κB) inhibitor SN50 as the positive control, and the changes in migration ability and apoptosis of the cells were examined using scratch assay and flow cytometry, respectively; the changes in the mRNA and protein expressions of CDH1, CDH2, caspase 3 and NF- κB were detected using RT-qPCR and Western blotting. ATAC-seq was used to analyze the changes in expressions of CDH1, CDH2, caspase 3 and NF-κB genes in the open chromatin.

Results: Treatment with GFC-medicated sera dose-dependently inhibited the migration (P < 0.05), increased apoptosis (P < 0.01), inhibited CDH2 and NF-κB mRNA expression (P < 0.05), and enhanced caspase 3 and CDH1 mRNA expressions (P < 0.01) in SKOV3/DDP cells. The effects of high-dose GFC-medicated serum were comparable to those of SN50 (P>0.05), but its effect for enhancing DH1 protein expression was weaker than that of SN50 (P < 0.01). GFC-medicated sera significantly lowered the expressions of NF-κB and CDH2 and increased CDH1 expression in the open chromatin without obviously affecting caspase 3 expression.

Conclusion: GFC- medicated sera inhibits the migration ability of SKOV3/DDP cells possibly by promoting cell apoptosis and caspase 3 and CDH1 expressions, inhibiting CDH2 and NF-κB expressions, and regulating the expressions of NF-κB, CDH2 and CDH1 in the open chromatin.

目的: 研究桂枝茯苓胶囊（GFC）抑制人卵巢癌转移的作用和潜在机制。

方法: 60只Wistar大鼠随机分为4组，15只/组：给药组分别灌胃给予4、8、16 g·kg-1·d-1剂量的GFC悬液5 d，分别制备GFC低、中、高剂量含药血清，空白组给予相同体积的生理盐水制备空白血清；卵巢癌耐顺铂SKOV3/DDP细胞分为空白血清组、不同剂量GFC含药血清组和NF-κB抑制剂SN50阳性对照组。采用划痕实验检测含药血清对迁移的影响，采用流式细胞术检测含药血清对凋亡的影响，采用RT-qPCR和Western blot检测含药血清对细胞中上皮表型E-钙粘蛋白（CDH1）、间质表型N-钙黏蛋白（CDH2）、caspase 3和NF-κB mRNA和蛋白表达的影响。采用ATAC-seq检测染色质开放区域CDH1、CDH2、caspase 3和NF-κB基因表达差异。

结果: GFC含药血清可剂量依赖性地抑制SKOV3/DDP细胞迁移，增加细胞凋亡（P < 0.05，P < 0.01）。随着含药血清剂量增加，其对CDH2和NF-κB的抑制作用，及其对CDH1和caspase 3的诱导作用均逐渐增强（P < 0.05，P < 0.01）。高剂量含药血清抑制SKOV3/DDP细胞迁移，诱导凋亡、caspase 3 mRNA和蛋白以及CDH1 mRNA表达，抑制CDH2和NF-κB mRNA和蛋白表达的作用与SN50相当（P>0.05），但诱导CDH1蛋白表达的作用弱于SN50（P < 0.01）。含药血清可减弱染色质开放区域NF-κB、CDH2基因表达，增强CDH1表达，但对caspase 3无影响。

结论: GFC含药血清抑制SKOV3/DDP迁移作用可能与其诱导凋亡、caspase 3和CDH1表达，抑制CDH2和NF-κB表达，调控染色质开放区域NF-κB、CDH2和CDH1表达有关。

Keywords: E-cadherin; Guizhi Fuling Capsule; N-cadherin; caspase 3; epithelial-mesenchymal transition; nuclear factor- kappa B; ovarian cancer.

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Figures

图 1
图 1
各组细胞迁移变化 Scratch assay for assessing cell migration changes in each group (Original magnification: ×40).
图 2
图 2
各组细胞迁移率变化 Migration rates of the cells in each group. *P < 0.05, **P < 0.01 vs blank sera group; ΔΔP < 0.01 vs SN50 group.
图 3
图 3
各组细胞凋亡变化 Flow cytometry for analyzing apoptosis of the cells in each group. A: Blank sera group. B: Low-dose GFC group. C: Medium-dose GFC group. D: High-dose GFC group. E: SN50 group.
图 4
图 4
各组细胞早期凋亡率变化 Early apoptotic rates in each group. **P < 0.01 vs blank sera group; ΔΔP < 0.01 vs SN50 group.
图 5
图 5
各组细胞CDH1、CDH2、caspase 3和NF-κB mRNA相对表达变化 Changes in relative expressions of CDH1, CDH2, caspase 3 and NF-κB mRNA in each group. *P < 0.05, **P < 0.01 vs blank sera group; ΔP < 0.05, ΔΔP < 0.01 vs SN50 group.
图 6
图 6
各组细胞CDH1、CDH2、caspase 3和NF- κB蛋白表达变化 Changes in expressions of CDH1, CDH2, caspase 3 and NF-κB proteins in each group.
图 7
图 7
各组细胞CDH1、CDH2、caspase 3和NF-κB蛋白相对表达变化 Changes in relative expression of CDH1, CDH2, caspase 3 and NF- κB proteins in each group. *P<0.05, **P<0.01 vs blank sera group; ΔP<0.05, ΔΔP<0.01 vs SN50 group.
图 8
图 8
桂枝茯苓胶囊含药血清对染色质开放区域CDH1、CDH2、caspase 3和NF-κB基因的影响 Effect of GFC-medicated sera on CDH1, CDH2, caspase 3 and NF-κB genes in the open areas of the chromatin. A: Peaks for DAR in all enrichment regions by ATAC-seq. B: Peaks for DAR in specific enrichment regions by ATAC-seq.
See this image and copyright information in PMC

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