MicroRNA-328 Negatively Regulates the Expression of Breast Cancer Resistance Protein (BCRP/ABCG2) in Human Cancer Cells

被引:260
作者
Pan, Yu-Zhuo [1 ]
Morris, Marilyn E. [1 ]
Yu, Ai-Ming [1 ]
机构
[1] SUNY Buffalo, Dept Pharmaceut Sci, Sch Pharm & Pharmaceut Sci, Buffalo, NY 14260 USA
基金
美国国家卫生研究院;
关键词
ABCG2; EXPRESSION; STEM-CELLS; MULTIDRUG-RESISTANCE; PROMOTER METHYLATION; MESSENGER-RNA; RECEPTOR; GENE; TRANSPORT; LINES; IDENTIFICATION;
D O I
10.1124/mol.108.054163
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Breast cancer resistance protein (BCRP/ABCG2) is a molecular determinant of pharmacokinetic properties of many drugs in humans. To understand post-transcriptional regulation of ABCG2 and the role of microRNAs (miRNAs) in drug disposition, we found that microRNA-328 (miR-328) might readily target the 3'-untranslated region (3'-UTR) of ABCG2 when considering target-site accessibility. We then noted 1) an inverse relation between the levels of miR-328 and ABCG2 in MCF-7 and MCF-7/MX100 breast cancer cells and 2) that miR-328 levels could be rescued in MCF-7/MX100 cells by transfection with miR-328 plasmid. Luciferase reporter assays showed that ABCG2 3'-UTR-luciferase activity was decreased more than 50% in MCF-7/MX100 cells after transfection with miR-328 plasmid, the activity was increased over 100% in MCF-7 cells transfected with a miR-328 antagomir, and disruption of miR-328 response element within ABCG2 3'-UTR led to a 3-fold increase in luciferase activity. Furthermore, the level of ABCG2 protein was down-regulated when miR-328 was over-expressed, and the level was up-regulated when miR-328 was inhibited by selective antagomir. Altered ABCG2 protein expression was associated with significantly declined or elevated levels of ABCG2 3'-UTR and coding sequence mRNAs, suggesting possible involvement of the mechanism of mRNA cleavage. Finally, miR-328-directed down-regulation of ABCG2 expression in MCF-7/MX100 cells resulted in an increased mitoxantrone sensitivity, as manifested by a significantly lower IC50 value (2.46 +/- 1.64 mu M) compared with the control (151 +/- 32 mu M). Together, these findings suggest that miR-328 targets ABCG2 3'-UTR and, consequently, controls ABCG2 protein expression and influences drug disposition in human breast cancer cells.
引用
收藏
页码:1374 / 1379
页数:6
相关论文
共 39 条
[1]   The functions of animal microRNAs [J].
Ambros, V .
NATURE, 2004, 431 (7006) :350-355
[2]   MicroRNAs: Genomics, biogenesis, mechanism, and function (Reprinted from Cell, vol 116, pg 281-297, 2004) [J].
Bartel, David P. .
CELL, 2007, 131 (04) :11-29
[3]   MicroRNA-298 and MicroRNA-328 Regulate Expression of Mouse β-Amyloid Precursor Protein-converting Enzyme 1 [J].
Boissonneault, Vincent ;
Plante, Isabelle ;
Rivest, Serge ;
Provost, Patrick .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (04) :1971-1981
[4]   Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes [J].
Calcagno, A. M. ;
Fostel, J. M. ;
To, K. K. W. ;
Salcido, C. D. ;
Martin, S. E. ;
Chewning, K. J. ;
Wu, C-P ;
Varticovski, L. ;
Bates, S. E. ;
Caplen, N. J. ;
Ambudkar, S. V. .
BRITISH JOURNAL OF CANCER, 2008, 98 (09) :1515-1524
[5]   Real-time quantification of microRNAs by stem-loop RT-PCR [J].
Chen, CF ;
Ridzon, DA ;
Broomer, AJ ;
Zhou, ZH ;
Lee, DH ;
Nguyen, JT ;
Barbisin, M ;
Xu, NL ;
Mahuvakar, VR ;
Andersen, MR ;
Lao, KQ ;
Livak, KJ ;
Guegler, KJ .
NUCLEIC ACIDS RESEARCH, 2005, 33 (20) :e179.1-e179.9
[6]   Tumour stem cells and drug resistance [J].
Dean, M ;
Fojo, T ;
Bates, S .
NATURE REVIEWS CANCER, 2005, 5 (04) :275-284
[7]   Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists [J].
Ebert, B ;
Seidel, A ;
Lampen, A .
CARCINOGENESIS, 2005, 26 (10) :1754-1763
[8]  
Ee PLR, 2004, MOL CANCER THER, V3, P1577
[9]   Identification of a novel estrogen response element in the breast cancer resistance protein (ABCG2) gene [J].
Ee, PLR ;
Kamalakaran, S ;
Tonetti, D ;
He, XL ;
Ross, DD ;
Beck, WT .
CANCER RESEARCH, 2004, 64 (04) :1247-1251
[10]   miRBase: microRNA sequences, targets and gene nomenclature [J].
Griffiths-Jones, Sam ;
Grocock, Russell J. ;
van Dongen, Stijn ;
Bateman, Alex ;
Enright, Anton J. .
NUCLEIC ACIDS RESEARCH, 2006, 34 :D140-D144