Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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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)
  • Received : 2016.07.28
  • Accepted : 2016.11.15
  • Published : 2017.09.01
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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

References

  1. 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. https://doi.org/10.4143/crt.2015.436
  2. 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. https://doi.org/10.1126/science.293.5538.2163a
  3. 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. https://doi.org/10.1172/JCI35660
  4. Boultwood, J. and Wainscoat, J. S. (2007) Gene silencing by DNA methylation in haematological malignancies. Br. J. Haematol. 138, 3-11. https://doi.org/10.1111/j.1365-2141.2007.06604.x
  5. 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. https://doi.org/10.1038/leu.2015.168
  6. Jabbour, E. and Kantarjian, H. (2014) Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. Am. J. Hematol. 89, 547-556. https://doi.org/10.1002/ajh.23691
  7. 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. https://doi.org/10.1038/sj.onc.1206928
  8. 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. https://doi.org/10.4149/neo_2015_115
  9. 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. https://doi.org/10.1371/journal.pone.0102221
  10. Lalevee, S. and Feil, R. (2015) Long noncoding RNAs in human disease:emerging mechanisms and therapeutic strategies. Epigenomics 7, 877-879. https://doi.org/10.2217/epi.15.55
  11. 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. https://doi.org/10.1371/journal.pone.0114586
  12. 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. https://doi.org/10.1038/srep32231
  13. 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. https://doi.org/10.1177/153303461000900109
  14. 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. https://doi.org/10.1046/j.1365-2443.2000.00320.x
  15. 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. https://doi.org/10.18632/oncotarget.7569
  16. 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. https://doi.org/10.1016/j.cell.2011.07.014
  17. 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. https://doi.org/10.1126/science.289.5486.1938
  18. 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. https://doi.org/10.1179/1607845413Y.0000000094
  19. 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. https://doi.org/10.1002/path.2638
  20. Takahashi, N. and Miura, M. (2011) Therapeutic drug monitoring of imatinib for chronic myeloid leukemia patients in the chronic phase. Pharmacology 87, 241-248. https://doi.org/10.1159/000324900
  21. 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. https://doi.org/10.1016/j.febslet.2010.10.008
  22. Tauchi, T. and Ohyashiki, K. (2004) Molecular mechanisms of resistance of leukemia to imatinib mesylate. Leuk. Res. 28 Suppl 1, S39-S45. https://doi.org/10.1016/j.leukres.2003.10.007
  23. Wei, G., Rafiyath, S. and Liu, D. (2010) First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J. Hematol. Oncol. 3, 47. https://doi.org/10.1186/1756-8722-3-47
  24. Xia, H. and Hui, K. M. (2014) Mechanism of cancer drug resistance and the involvement of noncoding RNAs. Curr. Med. Chem. 21, 3029-3041. https://doi.org/10.2174/0929867321666140414101939
  25. 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. https://doi.org/10.1186/1471-2407-13-469
  26. 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. https://doi.org/10.1371/journal.pone.0065309
  27. 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. https://doi.org/10.1210/en.2009-0657
  28. 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. https://doi.org/10.1210/jc.2003-030222
  29. 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. https://doi.org/10.1371/journal.pone.0060034

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