MicroRNA-873 mediates multidrug resistance in ovarian cancer cells by targeting ABCB1
Ovarian cancer is commonly treated with cisplatin and paclitaxel combination chemotherapy; however, ovarian cancer cells often develop resistance to these drugs. Increasingly, microRNAs (miRNAs) including miR-873 have been implicated in drug resistance in many cancers, but the role of miR-873 in ovarian cancer remains unknown. MTT cell viability assays revealed that the sensitivities of ovarian cancer lines to cisplatin and paclitaxel increased following transfection with miR-873 (P < 0.05). After predicting the miR-873 binding region in the 3′-untranslated region of ABCB1, dual-luciferase reporter assay confirmed this prediction. RT-PCR and Western blotting revealed that MDR1 expression was significantly downregulated after transfection with miR-873 and upregulated after transfection with anti-miR-873 at both mRNA and protein levels compared to negative controls (P < 0.05). Experiments in a mouse xenograft model confirmed that intratumoral administration of miR-873 could enhance the efficacy of cisplatin in inhibiting tumor growth in ovarian cancer in vivo (P < 0.05). ABCB1 overexpression reduced sensitivities of ovarian cancer lines OVCAR3 and A2780 to cisplatin and paclitaxel, which can be reversed by miR-873 mimic transfection (P < 0.05). In summary, we demonstrated that overexpression of miR-873 increased the sensitivity of ovarian cancer cells to cisplatin and paclitaxel by targeting MDR1 expression. Our findings suggest that combination therapies with chemotherapy agents and miR-873 may suppress drug resistance in ovarian cancer.
KeywordsABCB1 miR-873 Drug resistance Cisplatin Ovarian cancer
This work was supported by Liaoning Science and Technology Grant (2013021077) and the Natural Scientific Foundation of China (No. 81472502).
Compliance with ethical standards
Conflicts of interest
Z-H Z conceived the study and analyzed interpretation. D-D W, X-S L, X-N M, and JY carried out the experiments and analyzed the data. Z-H Z wrote the first and final draft of the manuscript. All authors read and approved the final manuscript.
- 14.Vilanova-Costa CA, Porto HK, Pereira LC, Carvalho BP, Dos Santos WB, Silveira-Lacerda EP. MDR1 and cytochrome P450 gene-expression profiles as markers of chemosensitivity in human chronic myelogenous leukemia cells treated with cisplatin and Ru(III) metallocomplexes. Biol Trace Elem Res. 2015;163(1-2):39–47.CrossRefPubMedGoogle Scholar
- 21.Sparreboom A, Scripture CD, Trieu V, Williams PJ, De T, Yang A, et al. Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol). Clin Cancer Res. 2005;11(11):4136–43.CrossRefPubMedGoogle Scholar
- 22.Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12(4):1317–24.CrossRefPubMedGoogle Scholar
- 25.Cui H, Zhang AJ, Chen M, Liu JJ. ABC Transporter Inhibitors in Reversing Multidrug Resistance to Chemotherapy. Curr Drug Targets. 2015;16(12):1356–71.Google Scholar
- 32.Wu X, Bhayani MK, Dodge CT, Nicoloso MS, Chen Y, Yan X, et al. Coordinated targeting of the EGFR signaling axis by microRNA-27a*. Oncotarget. 2013;4(9):1388–98.Google Scholar