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http://dx.doi.org/10.4062/biomolther.2016.162

LncRNA MEG3 Regulates Imatinib Resistance in Chronic Myeloid Leukemia via Suppressing MicroRNA-21  

Zhou, Xiangyu (Department of Vascular and Thyroid, the Affiliated Hospital of Southwest Medical University)
Yuan, Ping (Department of Neurology, the Affiliated Hospital of Southwest Medical University)
Liu, Qi (Department of Pediatrics, Nanchong Central Hospital)
Liu, Zhiqiang (Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center)
Publication Information
Biomolecules & Therapeutics / v.25, no.5, 2017 , pp. 490-496 More about this Journal
Abstract
Imatinib resistance has become a major clinical problem for chronic myeloid leukemia. The aim of the present study was to investigate the involvement of MEG3, a lncRNA, in imatinib resistance and demonstrate its underlying mechanisms. RNAs were extracted from CML patients' peripheral blood cells and human leukemic K562 cells, and the expression of MEG3 was measured by RT-qPCR. Cell proliferation and cell apoptosis were evaluated. Western blotting was used to measure the protein expression of several multidrug resistant transporters. Luciferase reporter assay was performed to determine the binding between MEG3 and miR-21. Our results showed that MEG3 was significantly decreased in imatinib-resistant CML patients and imatinib-resistant K562 cells. Overexpression of MEG3 in imatinib-resistant K562 cells markedly decreased cell proliferation, increased cell apoptosis, reversed imatinib resistance, and reduced the expression of MRP1, MDR1, and ABCG2. Interestingly, MEG3 binds to miR-21. MEG3 and miR-21 were negatively correlated in CML patients. In addition, miR-21 mimics reversed the phenotype of MEG3-overexpression in imatinib-resistant K562 cells. Taken together, MEG3 is involved in imatinib resistance in CML and possibly contributes to imatinib resistance through regulating miR-21, and subsequent cell proliferation, apoptosis and expression of multidrug resistant transporters.
Keywords
Chronic myeloid leukemia; Imatinib; Drug resistance; MEG3; MiR-21;
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1 Takahashi, N. and Miura, M. (2011) Therapeutic drug monitoring of imatinib for chronic myeloid leukemia patients in the chronic phase. Pharmacology 87, 241-248.   DOI
2 Tano, K., Mizuno, R., Okada, T., Rakwal, R., Shibato, J., Masuo, Y., Ijiri, K. and Akimitsu, N. (2010) MALAT-1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS Lett. 584, 4575-4580.   DOI
3 Arora, R., Sharma, M., Monif, T. and Iyer, S. (2016) A multi-centric bioequivalence trial in Ph+ chronic myeloid leukemia patients to assess bioequivalence and safety evaluation of generic imatinib mesylate 400mg tablets. Cancer Res. Treat. 48, 1120-1129.   DOI
4 Barthe, C., Cony-Makhoul, P., Melo, J. V. and Mahon, J. R. (2001) Roots of clinical resistance to STI-571 cancer therapy. Science 293, 2163.   DOI
5 Bellodi, C., Lidonnici, M. R., Hamilton, A., Helgason, G. V., Soliera, A. R., Ronchetti, M., Galavotti, S., Young, K. W., Selmi, T., Yacobi, R., Van Etten, R. A., Donato, N., Hunter, A., Dinsdale, D., Tirro, E., Vigneri, P., Nicotera, P., Dyer, M. J., Holyoake, T., Salomoni, P. and Calabretta, B. (2009) Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosomepositive cells, including primary CML stem cells. J. Clin. Invest. 119, 1109-1123.   DOI
6 Boultwood, J. and Wainscoat, J. S. (2007) Gene silencing by DNA methylation in haematological malignancies. Br. J. Haematol. 138, 3-11.   DOI
7 Hughes, T. P., Saglio, G., Quintas-Cardama, A., Mauro, M. J., Kim, D. W., Lipton, J. H., Bradley-Garelik, M. B., Ukropec, J. and Hochhaus, A. (2015) BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase. Leukemia 29, 1832-1838.   DOI
8 Jabbour, E. and Kantarjian, H. (2014) Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. Am. J. Hematol. 89, 547-556.   DOI
9 Salizzato, V., Borgo, C., Cesaro, L., Pinna, L. A. and Donella-Deana, A. (2016) Inhibition of protein kinase CK2 by CX-5011 counteracts imatinib-resistance preventing rpS6 phosphorylation in chronic myeloid leukaemia cells: new combined therapeutic strategies. Oncotarget 7, 18204-18218.   DOI
10 Miyoshi, N., Wagatsuma, H., Wakana, S., Shiroishi, T., Nomura, M., Aisaka, K., Kohda, T., Surani, M. A., Kaneko-Ishino, T. and Ishino, F. (2000) Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q. Genes Cells 5, 211-220.   DOI
11 Salmena, L., Poliseno, L., Tay, Y., Kats, L. and Pandolfi, P. P. (2011) A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146, 353-358.   DOI
12 Schindler, T., Bornmann, W., Pellicena, P., Miller, W. T., Clarkson, B. and Kuriyan, J. (2000) Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289, 1938-1942.   DOI
13 Silveira, R. A., Fachel, A. A., Moreira, Y. B., De Souza, C. A., Costa, F. F., Verjovski-Almeida, S. and Pagnano, K. B. (2014) Protein-coding genes and long noncoding RNAs are differentially expressed in dasatinib-treated chronic myeloid leukemia patients with resistance to imatinib. Hematology 19, 31-41.   DOI
14 Taft, R. J., Pang, K. C., Mercer, T. R., Dinger, M. and Mattick, J. S. (2010) Non-coding RNAs: regulators of disease. J. Pathol. 220, 126-139.   DOI
15 Xu, G., Zhang, Y., Wei, J., Jia, W., Ge, Z., Zhang, Z. and Liu, X. (2013) MicroRNA-21 promotes hepatocellular carcinoma HepG2 cell proliferation through repression of mitogen-activated protein kinasekinase 3. BMC cancer 13, 469.   DOI
16 Tauchi, T. and Ohyashiki, K. (2004) Molecular mechanisms of resistance of leukemia to imatinib mesylate. Leuk. Res. 28 Suppl 1, S39-S45.   DOI
17 Wei, G., Rafiyath, S. and Liu, D. (2010) First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J. Hematol. Oncol. 3, 47.   DOI
18 Xia, H. and Hui, K. M. (2014) Mechanism of cancer drug resistance and the involvement of noncoding RNAs. Curr. Med. Chem. 21, 3029-3041.   DOI
19 Yang, Y., Li, H., Hou, S., Hu, B., Liu, J. and Wang, J. (2013) The noncoding RNA expression profile and the effect of lncRNA AK126698 on cisplatin resistance in non-small-cell lung cancer cell. PLoS ONE 8, e65309.   DOI
20 Zhang, X., Rice, K., Wang, Y., Chen, W., Zhong, Y., Nakayama, Y., Zhou, Y. and Klibanski, A. (2010) Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions. Endocrinology 151, 939-947.   DOI
21 Zhang, X., Zhou, Y., Mehta, K. R., Danila, D. C., Scolavino, S., Johnson, S. R. and Klibanski, A. (2003) A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells. J. Clin. Endocrinol. Metab. 88, 5119-5126.   DOI
22 Liu, J., Wan, L., Lu, K., Sun, M., Pan, X., Zhang, P., Lu, B., Liu, G. and Wang, Z. (2015) The long noncoding RNA MEG3 contributes to cisplatin resistance of human lung adenocarcinoma. PLoS ONE 10, e0114586.   DOI
23 Zhi, F., Dong, H., Jia, X., Guo, W., Lu, H., Yang, Y., Ju, H., Zhang, X. and Hu, Y. (2013) Functionalized graphene oxide mediated adriamycin delivery and miR-21 gene silencing to overcome tumor multidrug resistance in vitro. PLoS ONE 8, e60034.   DOI
24 Ji, P., Diederichs, S., Wang, W., Boing, S., Metzger, R., Schneider, P. M., Tidow, N., Brandt, B., Buerger, H., Bulk, E., Thomas, M., Berdel, W. E., Serve, H. and Muller-Tidow, C. (2003) MALAT-1, a novel noncoding RNA, and thymosin ${\beta}4$ predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22, 8031-8041.   DOI
25 Jurkovicova, D., Lukackova, R., Magyerkova, M., Kulcsar, L., Krivjanska, M., Krivjansky, V. and Chovanec, M. (2015) microRNA expression profiling as supportive diagnostic and therapy prediction tool in chronic myeloid leukemia. Neoplasma 62, 949-958.   DOI
26 Kang, Y., Hodges, A., Ong, E., Roberts, W., Piermarocchi, C. and Paternostro, G. (2014) Identification of drug combinations containing imatinib for treatment of BCR-ABL+ leukemias. PLoS ONE 9, e102221.   DOI
27 Lalevee, S. and Feil, R. (2015) Long noncoding RNAs in human disease:emerging mechanisms and therapeutic strategies. Epigenomics 7, 877-879.   DOI
28 Liu, Y., Li, Y., Li, N., Teng, W., Wang, M., Zhang, Y. and Xiao, Z. (2016) TGF-${\beta}1$ promotes scar fibroblasts proliferation and transdifferentiation via up-regulating MicroRNA-21. Sci. Rep. 6, 32231.   DOI
29 Mei, M., Ren, Y., Zhou, X., Yuan, X. B., Han, L., Wang, G. X., Jia, Z., Pu, P. Y., Kang, C. S. and Yao, Z. (2010) Downregulation of miR-21 enhances chemotherapeutic effect of taxol in breast carcinoma cells. Technol. Cancer Res. Treat. 9, 77-86.   DOI