Journal
ONCOTARGET
Volume 8, Issue 51, Pages 88645-88657Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20435
Keywords
uPAR; miR-17-5p; miR-20a; DR5; apoptosis
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Funding
- Major State Basic Research Development Program of China (973 Program) [2014CB542602]
- Chinese Academy of Sciences [XDPB0304]
- National Natural Science Foundation of China [81621091, 81471960, 81761128002, 31230026, 81672815]
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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 of 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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