期刊
GYNECOLOGIC ONCOLOGY
卷 141, 期 3, 页码 592-601出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ygyno.2015.11.034
关键词
MiR-302; Breast cancer; BCRP; Drug resistance
资金
- National Natural Science Foundation of China [81173092]
- Shenyang ST Projects [F14-232-6-05]
- Program for Liaoning Innovative Research Team in University [LT2014016]
Objective. BCRP is overexpressed in many tumors and mediates multidrug resistance in breast cancer. In this study, we determined the involvement of miR-302S in the development of drug resistance in breast cancer. Methods. The differential miRNA expression profiling in parental MCF-7 cells and its derivative mitoxantrone (MX)-resistant MCF-7 (MCF-7/MX) cells was determined by the microarray analysis. The levels of miR-3025 family and BCRP mRNA expression were determined by using Quantitative Real-Time PCR. The targeting effect between the individuals of miR-302S and BCRP mRNA-3'UTR were detected by dual-luciferase reporter assay. Proteins of BCRP are represented by Western blot assay. Cell viability was assessed by MTS assay. Efflux capacity was evaluated using flow cytometry. Results. The miR-302S family including miR-302a, miR-302b, miR-302c, and miR-302d was significantly down-regulated in BCRP-overexpressing MCF-7/MX cells. Luciferase activity assay showed that miR-302 inhibited BCRP expression by targeting the 3'-untranslated region (UTR) of the BCRP mRNA. Overexpression of miR-302 increased intracellular accumulation of MX and sensitized breast cancer cells to MX. Furthermore, intratumoral injection of miR-302 potentiated the inhibitory effect of MX on tumor growth in mice transplanted with MCF-7/MX cells. Most importantly, miR-302S produced stronger effects than each individual member alone. Conclusions. These findings suggest that miR-302 inhibits BCRP expression via targeting the 3'-UTR of BCRP mRNA. miR-302 members may cooperatively downregulate BCRP expression to increase chemosensitivity of breast cancer cells. miR-302 gene cluster may be a potential target for reversing BCRP-mediated chemoresistance in breast cancer. (C) 2016 Elsevier Inc. All rights reserved.
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