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ZFX Facilitates Cell Proliferation and Imatinib Resistance in Chronic Myeloid Leukemia Cells

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Abstract

Zinc finger protein, X-linked (ZFX) mediates the development and progression of human cancers. However, its potential role in chronic myeloid leukemia (CML) is still unknown. The ZFX expression was significantly increased in CML patients and cell lines. Based on loss-of-function experiments in CML cells, we found that knockdown of ZFX expression impaired cell proliferation and induced mitotic arrest in G0/G1 stage and apoptosis. In addition, ZFX silencing sensitized CML cells to imatinib treatment. Further, phospho-Akt (p-Akt), CyclinD1, CyclinE1, and Bcl-2 were downregulated, and Caspase-3 was upregulated in ZFX-silenced cells. In summary, our data suggest that ZFX is a novel oncogene promoting cell proliferation and inducing imatinib resistance via PI3K/Akt signaling pathway. ZFX may represent a potential therapeutic target in CML.

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References

  1. Apperley, J. F. (2015). Chronic myeloid leukaemia. Lancet, 385(9976), 1447–1459.

    Article  PubMed  Google Scholar 

  2. Ren, R. (2005). Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nature Reviews Cancer, 5(3), 172–183.

    Article  CAS  PubMed  Google Scholar 

  3. Steelman, L. S., Pohnert, S. C., Shelton, J. G., Franklin, R. A., Bertrand, F. E., & McCubrey, J. A. (2004). JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 18(2), 189–218.

    Article  CAS  PubMed  Google Scholar 

  4. Druker, B. J., Talpaz, M., Resta, D. J., Peng, B., Buchdunger, E., Ford, J. M., et al. (2001). Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. The New England Journal of Medicine, 344(14), 1031–1037.

    Article  CAS  PubMed  Google Scholar 

  5. Kantarjian, H. M., Cortes, J. E., O’Brien, S., Giles, F., Garcia-Manero, G., Faderl, S., et al. (2003). Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: High incidence of early complete and major cytogenetic responses. Blood, 101(1), 97–100.

    Article  CAS  PubMed  Google Scholar 

  6. Hochhaus, A., Kreil, S., Corbin, A. S., La Rosee, P., Muller, M. C., Lahaye, T., et al. (2002). Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia, 16(11), 2190–2196.

    Article  CAS  PubMed  Google Scholar 

  7. Jabbour, E. J., Cortes, J. E., & Kantarjian, H. M. (2013). Resistance to tyrosine kinase inhibition therapy for chronic myelogenous leukemia: A clinical perspective and emerging treatment options. Clinical Lymphoma Myeloma and Leukemia, 13(5), 515–529.

    Article  CAS  Google Scholar 

  8. Laity, J. H., Lee, B. M., & Wright, P. E. (2001). Zinc finger proteins: New insights into structural and functional diversity. Current Opinion in Structural Biology, 11(1), 39–46.

    Article  CAS  PubMed  Google Scholar 

  9. Poloumienko, A. (2004). Cloning and comparative analysis of the bovine, porcine, and equine sex chromosome genes ZFX and ZFY. Genome Génome/Conseil National De Recherches Canada, 47(1), 74–83.

    Article  CAS  Google Scholar 

  10. Cellot, S., & Sauvageau, G. (2007). Zfx: At the crossroads of survival and self-renewal. Cell, 129(2), 239–241.

    Article  CAS  PubMed  Google Scholar 

  11. Galan-Caridad, J. M., Harel, S., Arenzana, T. L., Hou, Z. E., Doetsch, F. K., Mirny, L. A., et al. (2007). Zfx controls the self-renewal of embryonic and hematopoietic stem cells. Cell, 129(2), 345–357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Harel, S., Tu, E. Y., Weisberg, S., Esquilin, M., Chambers, S. M., Liu, B., et al. (2012). ZFX controls the self-renewal of human embryonic stem cells. PLoS One, 7(8), e42302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jiang, H., Zhang, L., Liu, J., Chen, Z., Na, R., Ding, G., et al. (2012). Knockdown of zinc finger protein X-linked inhibits prostate cancer cell proliferation and induces apoptosis by activating caspase-3 and caspase-9. Cancer Gene Therapy, 19(10), 684–689.

    Article  CAS  PubMed  Google Scholar 

  14. Jiang, M., Xu, S., Yue, W., Zhao, X., Zhang, L., Zhang, C., et al. (2012). The role of ZFX in non-small cell lung cancer development. Oncology Research, 20(4), 171–178.

    Article  PubMed  Google Scholar 

  15. Wu, S., Lao, X. Y., Sun, T. T., Ren, L. L., Kong, X., Wang, J. L., et al. (2013). Knockdown of ZFX inhibits gastric cancer cell growth in vitro and in vivo via downregulating the ERK-MAPK pathway. Cancer Letters, 337(2), 293–300.

    Article  CAS  PubMed  Google Scholar 

  16. Zhu, Z., Li, K., Xu, D., Liu, Y., Tang, H., Xie, Q., et al. (2013). ZFX regulates glioma cell proliferation and survival in vitro and in vivo. Journal of Neuro-oncology, 112(1), 17–25.

    Article  CAS  PubMed  Google Scholar 

  17. Yang, H., Lu, Y., Zheng, Y., Yu, X., Xia, X., He, X., et al. (2014). shRNA-mediated silencing of ZFX attenuated the proliferation of breast cancer cells. Cancer Chemotherapy and Pharmacology, 73(3), 569–576.

    Article  CAS  PubMed  Google Scholar 

  18. Weisberg, S. P., Smith-Raska, M. R., Esquilin, J. M., Zhang, J., Arenzana, T. L., Lau, C. M., et al. (2014). ZFX controls propagation and prevents differentiation of acute T-lymphoblastic and myeloid leukemia. Cell Reports, 6(3), 528–540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Qi, J., Peng, H., Gu, Z. L., Liang, Z. Q., & Yang, C. Z. (2004). Establishment of an imatinib resistant cell line K562/G01 and its characterization. Zhonghua Xue Ye Xue Za Zhi, 25(6), 337–341.

    CAS  PubMed  Google Scholar 

  20. Conde, I., Pabon, D., Jayo, A., Lastres, P., & Gonzalez-Manchon, C. (2010). Involvement of ERK1/2, p38 and PI3K in megakaryocytic differentiation of K562 cells. European Journal of Haematology, 84(5), 430–440.

    Article  CAS  PubMed  Google Scholar 

  21. Yin, J., Jiang, Y., Wu, H., Wang, J., Zhang, S., & Liu, H. (2015). Overexpression of ZFX and its involvement in squamous cell carcinoma of the tongue. Oncology Reports, 33(1), 141–148.

    CAS  PubMed  Google Scholar 

  22. Lai, K. P., Chen, J., He, M., Ching, A. K., Lau, C., Lai, P. B., et al. (2014). Overexpression of ZFX confers self-renewal and chemoresistance properties in hepatocellular carcinoma. International Journal of Cancer, 135(8), 1790–1799.

    Article  CAS  PubMed  Google Scholar 

  23. Li, K., Zhu, Z. C., Liu, Y. J., Liu, J. W., Wang, H. T., Xiong, Z. Q., et al. (2013). ZFX knockdown inhibits growth and migration of non-small cell lung carcinoma cell line H1299. International Journal of Clinical and Experimental Pathology, 6(11), 2460–2467.

    PubMed  PubMed Central  Google Scholar 

  24. Fang, Q., Fu, W. H., Yang, J., Li, X., Zhou, Z. S., Chen, Z. W., et al. (2014). Knockdown of ZFX suppresses renal carcinoma cell growth and induces apoptosis. Cancer Genetics, 207(10–12), 461–466.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang, H., Chang, G., Wang, J., Lin, Y., Ma, L., & Pang, T. (2013). CUEDC2 sensitizes chronic myeloid leukemic cells to imatinib treatment. Leukemia Research, 37(11), 1583–1591.

    Article  CAS  PubMed  Google Scholar 

  26. Wang, H., Yu, J., Zhang, L., Xiong, Y., Chen, S., Xing, H., et al. (2014). RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells. Biochemical and Biophysical Research Communications, 446(4), 1204–1210.

    Article  CAS  PubMed  Google Scholar 

  27. Wang, Y., Jiang, Y., Bian, C., Dong, Y., Ma, C., Hu, X., et al. (2015). Overexpression of Hiwi inhibits the cell growth of chronic myeloid leukemia K562 cells and enhances their chemosensitivity to daunomycin. Cell Biochemistry and Biophysics, 73(1), 129–135.

    Article  CAS  Google Scholar 

  28. Fang, J., Yu, Z., Lian, M., Ma, H., Tai, J., Zhang, L., et al. (2012). Knockdown of zinc finger protein, X-linked (ZFX) inhibits cell proliferation and induces apoptosis in human laryngeal squamous cell carcinoma. Molecular and Cellular Biochemistry, 360(1–2), 301–307.

    Article  CAS  PubMed  Google Scholar 

  29. Palmer, C. J., Galan-Caridad, J. M., Weisberg, S. P., Lei, L., Esquilin, J. M., Croft, G. F., et al. (2014). Zfx facilitates tumorigenesis caused by activation of the Hedgehog pathway. Cancer Research, 74(20), 5914–5924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Burchert, A., Wang, Y., Cai, D., von, B. N., Paschka, P., Muller-Brusselbach, S., et al. (2005). Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia, 19(10), 1774–1782.

    Article  CAS  PubMed  Google Scholar 

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    Authors and Affiliations

    1. Department of Hematology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, 223300, China

      Jingjing Wu, Qian Wang, Yihan Ding, Zhikui Deng, Xueying Lu & Yufeng Li

    2. Department of Oncology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, 223300, China

      Bin Wei

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    1. Jingjing Wu
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    Correspondence to Yufeng Li.

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    Jingjing Wu and Bin Wei have contributed equally to this work and should be considered co-first authors.

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    Wu, J., Wei, B., Wang, Q. et al. ZFX Facilitates Cell Proliferation and Imatinib Resistance in Chronic Myeloid Leukemia Cells. Cell Biochem Biophys 74, 277–283 (2016). https://doi.org/10.1007/s12013-016-0725-x

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    • DOI: https://doi.org/10.1007/s12013-016-0725-x

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