Oncotarget

Research Papers:

Urokinase-type plasminogen activator receptor inhibits apoptosis in triple-negative breast cancer through miR-17/20a suppression of death receptors 4 and 5

Xin Li, Bo Wu, Lizhao Chen, Ying Ju, Changfei Li and Songdong Meng _

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Oncotarget. 2017; 8:88645-88657. https://doi.org/10.18632/oncotarget.20435

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Abstract

Xin Li1,*, Bo Wu1,*, Lizhao Chen1, Ying Ju1, Changfei Li1 and Songdong Meng1,2

1CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China

2College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China

*These authors have contributed equally to this work

Correspondence to:

Songdong Meng, email: mengsd@im.ac.cn

Changfei Li, email: lichangfei2006@163.com

Keywords: uPAR,miR-17-5p, miR-20a, DR5, apoptosis

Received: December 21, 2016    Accepted: July 23, 2017    Published: August 24, 2017

ABSTRACT

Dissection and understanding of the molecular pathways driving triple-negative breast cancer (TNBC) are urgently needed to develop efficient tailored therapies. Aside from cell invasion and metastasis, the urokinase-type plasminogen activator receptor (uPAR) has been linked to apoptosis resistance in breast tumors. We explored the mechanism of uPAR-disrupted apoptosis in breast cancer. We found that depletion of uPAR by RNAi increases death receptor 4 (DR4) and death receptor 5 (DR5) expression and triggers TRAIL-induced apoptosis in TNBC cells. The microRNAs miR-17-5p and miR-20a inhibit cell apoptosis via suppression DR4/DR5. We provide evidence that uPAR enhances miR-17-5p/20a expression through upregulation of c-myc. Blocking miR-17-5p/20a with antagomiRNA suppressed the growth of uPAR-overexpressing breast tumor xenografts in mice. These results indicate that uPAR suppresses cell apoptosis by inhibiting the c-myc-miR-17/5p/20a-DR4/DR5 pathway. Therapy directed at uPAR-induced miR-17/20a is a potential option for breast cancer and TNBC.


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