miRNA-34a is associated with docetaxel resistance in human breast cancer cells

被引:181
作者
Kastl, L. [1 ]
Brown, I. [1 ]
Schofield, A. C. [1 ]
机构
[1] Univ Aberdeen, Sch Med, Sch Med & Dent, Div Appl Med,Coll Life Sci & Med, Aberdeen AB25 2ZD, Scotland
关键词
Breast cancer cells; Docetaxel; Drug resistance; miRNA; CYCLIN D1; CARCINOMA CELLS; DOWN-REGULATION; MULTIDRUG-RESISTANCE; TARGETING BCL2; MCF-7; CELLS; PC3; APOPTOSIS; EXPRESSION; MIR-34A;
D O I
10.1007/s10549-011-1424-3
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Docetaxel is a chemotherapy drug to treat breast cancer, however as with many chemotherapeutic drugs resistance to docetaxel occurs in 50% of patients, and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulation through microRNAs (miRNA) has been shown to play an important role in cancer drug resistance. By directly targeting mRNA, miRNAs are able to inhibit genes that are necessary for signalling pathways or drug induced apoptosis rendering cells drug resistant. This study investigated the role of differential miRNA expression in two in vitro breast cancer cell line models (MCF-7, MDA-MB-231) of acquired docetaxel resistance. MiRNA microarray analysis identified 299 and 226 miRNAs altered in MCF-7 and MDA-MB-231 docetaxel-resistant cells, respectively. Docetaxel resistance was associated with increased expression of miR-34a and miR-141 and decreased expression of miR-7, miR-16, miR-30a, miR-125a-5p, miR-126. Computational target prediction revealed eight candidate genes targeted by these miRNAs. Quantitative PCR and western analysis confirmed decreased expression of two genes, BCL-2 and CCND1, in docetaxel-resistant cells, which are both targeted by miR-34a. Modulation of miR-34a expression was correlated with BCL-2 and cyclin D1 protein expression changes and a direct interaction of miR-34a with BCL-2 was shown by luciferase assay. Inhibition of miR-34a enhanced response to docetaxel in MCF-7 docetaxel-resistant cells, whereas overexpression of miR-34a conferred resistance in MCF-7 docetaxel-sensitive cells. This study is the first to show differences in miRNA expression, in particular, increased expression of miR-34a in an acquired model of docetaxel resistance in breast cancer. This serves as a mechanism of acquired docetaxel resistance in these cells, possibly through direct interactions with BCL-2 and CCND1, therefore presenting a potential therapeutic target for the treatment of docetaxel-resistant breast cancer.
引用
收藏
页码:445 / 454
页数:10
相关论文
共 53 条
[1]   Identification of human microRNA targets from isolated argonaute protein complexes [J].
Beitzinger, Michaela ;
Peters, Lasse ;
Zhu, Jia Yun ;
Kremmer, Elisabeth ;
Meister, Gunter .
RNA BIOLOGY, 2007, 4 (02) :76-84
[2]  
Bilalovic Nurija, 2004, Bosn J Basic Med Sci, V4, P5
[3]   Overexpression of cyclin D1 promotes tumor cell growth and confers resistance to cisplatin-mediated apoptosis in an elastase-myc transgene-expressing pancreatic tumor cell line [J].
Biliran, H ;
Wang, Y ;
Banerjee, X ;
Xu, HM ;
Heng, H ;
Thakur, A ;
Bollig, A ;
Sarkar, FH ;
Liao, JD .
CLINICAL CANCER RESEARCH, 2005, 11 (16) :6075-6086
[4]   p53-mediated activation of miRNA34 candidate tumor-suppressor genes [J].
Bommer, Guido T. ;
Gerin, Isabelle ;
Feng, Ying ;
Kaczorowski, Andrew J. ;
Kuick, Rork ;
Love, Robert E. ;
Zhai, Yali ;
Giordano, Thomas J. ;
Qin, Zhaohui S. ;
Moore, Bethany B. ;
MacDougald, Ormond A. ;
Cho, Kathleen R. ;
Fearon, Eric R. .
CURRENT BIOLOGY, 2007, 17 (15) :1298-1307
[5]  
Brown I, 2004, BREAST CANCER RES, V6, P601
[6]  
Cardoso Fatima, 2004, Clin Breast Cancer, V5, P364, DOI 10.3816/CBC.2004.n.043
[7]   Estrogen Receptor α Controls a Gene Network in Luminal-Like Breast Cancer Cells Comprising Multiple Transcription Factors and MicroRNAs [J].
Cicatiello, Luigi ;
Mutarelli, Margherita ;
Grober, Ohi M. V. ;
Paris, Ornella ;
Ferraro, Lorenzo ;
Ravo, Maria ;
Tarallo, Roberta ;
Luo, Shujun ;
Schroth, Gary P. ;
Seifert, Martin ;
Zinser, Christian ;
Chiusano, Maria Luisa ;
Traini, Alessandra ;
De Bortoli, Michele ;
Weisz, Alessandro .
AMERICAN JOURNAL OF PATHOLOGY, 2010, 176 (05) :2113-2130
[8]   miR-15 and miR-16 induce apoptosis by targeting BCL2 [J].
Cimmino, A ;
Calin, GA ;
Fabbri, M ;
Iorio, MV ;
Ferracin, M ;
Shimizu, M ;
Wojcik, SE ;
Aqeilan, RI ;
Zupo, S ;
Dono, M ;
Rassenti, L ;
Alder, H ;
Volinia, S ;
Liu, CG ;
Kipps, TJ ;
Negrini, M ;
Croce, CM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (39) :13944-13949
[9]   A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene [J].
Cole, Kristina A. ;
Attiyeh, Edward F. ;
Mosse, Yael P. ;
Laquaglia, Michael J. ;
Diskin, Sharon J. ;
Brodeur, Garrett M. ;
Maris, John M. .
MOLECULAR CANCER RESEARCH, 2008, 6 (05) :735-742
[10]  
El-Ahmady O, 2002, ANTICANCER RES, V22, P2493