1. Academic Validation
  2. MiR-873/PD-L1 axis regulates the stemness of breast cancer cells

MiR-873/PD-L1 axis regulates the stemness of breast cancer cells

  • EBioMedicine. 2019 Mar;41:395-407. doi: 10.1016/j.ebiom.2019.02.034.
Lanlan Gao 1 Qianqian Guo 1 Xiaoman Li 2 Xuan Yang 1 Haiwei Ni 1 Ting Wang 1 Qiong Zhao 1 Hai Liu 1 Yingying Xing 1 Tao Xi 3 Lufeng Zheng 4
Affiliations

Affiliations

  • 1 School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, People's Republic of China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
  • 2 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People's Republic of China.
  • 3 School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, People's Republic of China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: Xitao18@hotmail.com.
  • 4 School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, People's Republic of China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: zhlf@cpu.edu.cn.
Abstract

Background: Breast Cancer Stem Cells have self-renewal capability and are resistant to conventional chemotherapy. PD-L1 could promote the expression of stemness markers (OCT4 and Nanog) in breast Cancer Stem Cells. However, the mechanisms by which PD-L1 regulates the stemness of breast Cancer cells and PD-L1 is regulated in breast Cancer cells are still unclear.

Methods: Lentivirus Infection was used to construct stable cell lines. The correlation between PD-L1 and stemness markers expression was evaluated in clinical samples. Additionally, luciferase reporter assay combined with RNA-Fluorescence in situ hybridization (RNA-FISH) and RNA-binding protein immunoprecipitation (RIP) assays were used to verify the direct binding of miR-873 on PD-L1. Furthermore, flow cytometry, mammosphere formation combined with nude mouse tumor xenograft model were carried out to examine the effects of miR-873/PD-L1 axis on the stemness of breast Cancer cells. Finally, MTT assay was performed to determine the effects of miR-873/PD-L1 axis on drug resistance.

Findings: PD-L1 expression was positively correlated with the expression of stemness markers, and overexpression of PD-L1 contributed to chemoresistance and stemness-like properties in breast Cancer cells via activating PI3K/Akt and ERK1/2 pathways. Mechanistically, miR-873 inhibited PD-L1 expression through directly binding to its 3'-untranslated region (UTR), and miR-873 attenuated the stemness and chemoresistance of breast Cancer cells which was dependent on PD-L1 and the downstream PI3K/Akt and ERK1/2 signaling. Notably, the promotion of PD-L1 on the stemness and chemoresistance was enhanced by recombinant PD-1 (rPD-1), this effect was attenuated by PD-1/PD-L1 inhibitor.

Interpretation: miR-873/PD-L1 regulatory axis might serve as a therapeutic target to enhance the chemo-sensitivity and eliminate the stemness of breast Cancer cells. FUND: This work was supported by the National Nature Science Foundation of China, No. 81702957, China Postdoctoral Science Foundation, No. 2017M620230, the Postdoctoral Research Funding Scheme of Jiangsu Province (2017), No. 1701197B, and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

Keywords

Cancer stem cells; Drug resistance; ERK1/2; PD-L1; PI3K/Akt; miR-873.

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