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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 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.
Highlights
Urokinase plasminogen activator receptor is a highly glycosylated membraneanchored protein
Because TRAIL binds to the pro-apoptotic death receptor 4 (DR4) and death receptor 5 (DR5) and triggers the cell apoptosis pathway [21], we determined whether urokinase-type plasminogen activator receptor (uPAR) depletion influences DR4 and DR5
We found that uPAR induces miR-17-5p and miR-20a expression by upregulating the transcription factor c-myc, whereas miR-17-5p/20a inhibit breast cancer apoptosis by suppressing DR4 and DR5
Summary
Urokinase plasminogen activator receptor (uPAR) ( designated CD87) is a highly glycosylated membraneanchored protein. Along with its ligand urokinase-type plasminogen activator (uPA), uPAR is a signaling receptor that interacts with proteins such as integrins, vitronectin, LRP-related receptor, and others [3]. As a glycosylphosphatidylinositol-anchored (GPI-anchored) cell surface protein, uPAR relays its downstream signals via its co-receptors, including integrins and growth factor receptors (GFRs). These interactions activate the FAK, Src, ERK, and PI3K/AKT signaling pathways, which might induce an epithelial to mesenchymal transition (EMT), cell proliferation, and migration [3,4,5,6,7]
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