Involvement of miR-326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1

• Type of Material: Article
• Authors: Zhongxing Liang, Emory University; Hui Wu, Emory University; James Xia, GenoSensor Corporation; Yuhua Li, Emory University; Yawei Zhang, Emory University; Ke Huang, Emory University; Nicholas Wagar, Emory University; Younghyoun Yoon, Emory University; Heidi T. Cho, Emory University; Stefania Scala, IRCCS Istituto Nazionale Tumori Fondazione G Pascale; Hyunsuk Shim, Emory University
• Language: English
• Date: 2010-03-15
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.crossref.org/10.1016%2Fj.bcp.2009.10.017
• Title of Journal or Parent Work: Biochemical Pharmacology
• ISSN: 0006-2952
• Volume: 79
• Issue: 6
• Start Page: 817
• End Page: 824
• Grant/Funding Information: This study was financially supported by the Department of Defense Breast Cancer Program Concept Award (BC052118) to ZL as well as a Research Grant from NIH NCI (1R01CA109366) and the Georgia Cancer Coalition Distinguished Cancer Scholar Award to HS.
• Keywords: Breast cancer; MRP-1; microRNA; Multidrug resistance
• Research Categories: Health Sciences, Pharmacology; Chemistry, Biochemistry; Health Sciences, Oncology

Abstract

Multidrug resistance-associated protein (MRP-1/ABCC1) transports a wide range of therapeutic agents and may play a critical role in the development of multidrug resistance (MDR) in tumor cells. However, the regulation of MRP-1 remains controversial. To explore whether miRNAs are involved in the regulation of MRP-1 expression and modulate the sensitivity of tumor cells to chemotherapeutic agents, we analyzed miRNA expression levels in VP-16-resistant MDR cell line, MCF-7/VP, in comparison with its parent cell line, MCF-7, using a miRNA microarray. MCF-7/VP overexpressed MRP-1 mRNA and protein not MDR-1 and BCRP. miR-326 was downregulated in MCF-7/VP compared to MCF-7. Additionally, miR-326 was downregulated in a panel of advanced breast cancer tissues and consistent reversely with expression levels of MRP-1. Furthermore, the elevated levels of miR-326 in the mimics-transfected VP-16-resistant cell line, MCF-7/VP, downregulated MRP-1 expression and sensitized these cells to VP-16 and doxorubicin. These findings demonstrate for the first time the involvement of miRNAs in multidrug resistance mediated by MRP-1 and suggest that miR-326 may be an efficient agent for preventing and reversing MDR in tumor cells.