Extracellular Vesicles Carrying miR-887-3p Promote Breast Cancer Cell Drug Resistance by Targeting BTBD7 and Activating the Notch1/Hes1 Signaling Pathway

DISEASE MARKERS(2022)

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摘要
Objective. Chemoresistance remains the primary reason threatening the prognosis of breast cancer (BC) patients. Extracellular vesicles (EVs) contribute to chemoresistance by carrying microRNAs (miRNAs). This study investigated the mechanism of miR-887-3p mediated by EVs in BC cell drug resistance. Methods. MDA-MB-231-derived EVs were extracted and identified. BC cells were treated with different concentrations of doxorubicin, cisplatin, and fulvestrant, and the cell survival was evaluated. PKH26-labeled EVs were cocultured with BC cells, and the uptake of EVs was observed. miR-887-3p expression in BC cells and EVs was detected. After silencing miR-887-3p in MDA-MB-231 cells, BC cells were treated with EV-inhi to observe drug resistance. The target gene of miR-887-3p was predicted and verified. The levels of downstream Notch1/Hes1 pathway were detected. Xenograft experiment was conducted to evaluate the effect of EVs on the growth and drug resistance in vivo. Results. MDA-MB-231-derived EVs enhanced the drug resistance of BC cells. EVs carried miR-887-3p into BC cells. miR-887-3p expression was elevated in BC cells and EVs. miR-887-3p inhibition reduced the drug resistance of BC cells. miR-887-3p targeted BTBD7. Overexpression of BTBD7 partially reversed the drug resistance of BC cells caused by EV treatment. EV treatment increased the level of Notch1/Hes1, and overexpression of BTBD7 decreased the level of Notch1/Hes1. In vivo experiments further validated the results of in vitro experiments. Conclusion. EVs carrying miR-887-3p could target BTBD7 and activate the Notch1/Hes1 signaling pathway, thereby promoting BC cell drug resistance. This study may offer novel insights into BC treatment.
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