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Paeoniflorin Sensitizes Breast Cancer Cells to Tamoxifen by Downregulating microRNA-15b via the FOXO1/CCND1/β-Catenin Axis

Authors Wang Y, Wang Q, Li X, Luo G, Shen M, Shi J, Wang X, Tang L

Received 20 August 2020

Accepted for publication 12 December 2020

Published 22 January 2021 Volume 2021:15 Pages 245—257


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Anastasios Lymperopoulos

Yanhong Wang,1,2 Qian Wang,1 Xibei Li,3 Gongwen Luo,2 Mou Shen,2 Jia Shi,4 Xueliang Wang,5 Lu Tang6

1Department of Basic Medicine, Medical College of Yunnan University of Economics and Management, Kunming, Yunnan 650000, People’s Republic of China; 2Second Department of Internal Medicine, Chongming Branch of Yueyang Integrated Hospital of Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Chongming, Shanghai, 202150, People’s Republic of China; 3Department of Stomatology, Jining Medical College, Jining, Shandong 272000, People’s Republic of China; 4Department of Information, The First Affiliated Hospital of Naval Military Medical University (Shanghai Changhai Hospital), Shanghai 200433, People’s Republic of China; 5Department of Nephrology and Rheumatology, Zhaotong Traditional Chinese Medicine Hospital of Yunnan Province, Zhaotong, Yunnan 657000 People’s Republic of China; 6Department of Traditional Chinese Medicine, Kunming Second People’s Hospital, Kunming, Yunnan, 650000 People’s Republic of China

Correspondence: Lu Tang
Department of Traditional Chinese Medicine, Kunming Second People’s Hospital, No. 672 Longquan Road, Panlong District, Kunming, Yunnan 650000, People’s Republic of China

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.

Keywords: paeoniflorin, breast cancer, tamoxifen, microRNA-15b, FOXO1

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