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Paeoniflorin Sensitizes Breast Cancer Cells to Tamoxifen by Downregulating microRNA-15b via the FOXO1/CCND1/β-Catenin Axis
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2021-01-22 , DOI: 10.2147/dddt.s278002
Yanhong Wang 1, 2 , Qian Wang 1 , Xibei Li 3 , Gongwen Luo 2 , Mou Shen 2 , Jia Shi 4 , Xueliang Wang 5 , Lu Tang 6
Affiliation  

Background: Paeoniflorin (Pae) possesses anti-tumor activity in various malignancies. However, it is unclear whether Pae plays a sensitizer role in breast cancer (BC) and the molecular mechanisms involved in this process. Our oligonucleotide microarray revealed that microRNA (miR)-15b is the most significantly downregulated miRNA in MCF-7/4-hydroxytamoxifen (4-OHT) cells treated with Pae. This paper summarized the relevance of Pae in BC cell endocrine resistance to tamoxifen (Tam) and the molecular mechanisms involved miR-15b expression.
Materials and Methods: 4-OHT-resistant BC cell lines were developed and treated with different concentrations of Pae. Flow cytometry, lactose dehydrogenase activity, caspase-3 activity, colony formation, and EdU assays were carried out to assess the impact of Pae on BC cells. Differentially expressed miRNAs in BC cells treated with Pae were analyzed by microarray. Targeting mRNAs of screened miR-15b as well as the binding of forkhead box O1 (FOXO1) to the cyclin D1 (CCND1) promoter sequence were predicted through bioinformatics analysis. Finally, the expression of β-catenin signaling-related genes in cells was detected by Western blotting.
Results: Pae (100 μg/mL) inhibited the clonality and viability of BC cells, while enhancing apoptosis in vitro. Pae also repressed miR-15b expression. Overexpression of miR-15b restored the growth and resistance of BC cells to 4-OHT. Moreover, Pae promoted FOXO1 expression by downregulating miR-15b, thereby transcriptionally inhibiting CCND1 and subsequently blocking β-catenin signaling.
Conclusion: Pae inhibits 4-OHT resistance in BC cells by regulating the miR-15b/FOXO1/CCND1/β-catenin pathway.



中文翻译:

芍药苷通过 FOXO1/CCND1/β-连环蛋白轴下调 microRNA-15b,使乳腺癌细胞对他莫昔芬敏感

背景:芍药苷 (Pae) 在各种恶性肿瘤中具有抗肿瘤活性。然而,尚不清楚 Pae 是否在乳腺癌 (BC) 中发挥致敏作用以及参与该过程的分子机制。我们的寡核苷酸微阵列显示,在用 Pae 处理的 MCF-7/4-羟基三苯氧胺 (4-OHT) 细胞中,microRNA (miR)-15b 是最显着下调的 miRNA。本文总结了Pae在BC细胞对他莫昔芬(Tam)的内分泌抗性中的相关性以及涉及miR-15b表达的分子机制。
材料和方法:开发了耐 4-OHT 的 BC 细胞系,并用不同浓度的 Pae 处理。进行流式细胞术、乳糖脱氢酶活性、caspase-3 活性、集落形成和 EdU 测定以评估 Pae 对 BC 细胞的影响。通过微阵列分析用 Pae 处理的 BC 细胞中差异表达的 miRNA。通过生物信息学分析预测筛选的 miR-15b 的靶向 mRNA 以及叉头盒 O1 (FOXO1) 与细胞周期蛋白 D1 (CCND1) 启动子序列的结合。最后通过Western blotting检测细胞内β-catenin信号相关基因的表达。
结果:Pae (100 μg/mL) 抑制 BC 细胞的克隆性和活力,同时在体外增强细胞凋亡。Pae 还抑制 miR-15b 的表达。miR-15b 的过表达恢复了 BC 细胞的生长和对 4-OHT 的抗性。此外,Pae 通过下调 miR-15b 促进 FOXO1 的表达,从而在转录上抑制 CCND1 并随后阻断 β-catenin 信号传导。
结论: Pae通过调控miR-15b/FOXO1/CCND1/β-catenin通路抑制BC细胞4-OHT耐药。

更新日期:2021-01-22
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