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MicroRNA-153-3p enhances the sensitivity of chronic myeloid leukemia cells to imatinib by inhibiting B-cell lymphoma-2-mediated autophagy

Abstract

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease caused by abnormal DNA replication of bone marrow stem cells and chemotherapy resistance is a major obstacle to the effective treatment of patients with CML. Imatinib (IM), a tyrosine kinase inhibitor (TKI), is a first-line drug clinically used for CML. Mounting evidence has indicated that the dysregulation of microRNAs (miRNAs) is associated with the chemoresistance of CML. In this study, miR-153-3p, which had been implicated with numerous types of tumors, was identified to be downregulated in IM-resistant CML cells. Upregulation of miR-153-3p significantly increased IM sensitivity and decreased the survival rate of IM-resistant CML cells, whereas downregulation of miR-153-3p attenuated these effects in IM-resistant CML cells. Upregulated miR-153-3p could decrease the autophagy caused by IM in IM-resistant CML cells. Dual-luciferase reporter assays confirmed that Bcl-2 is a direct target of miR-153-3p. Bcl-2 restoration reversed the increased sensitivity to IM induced by miR-153-3p-mimic transfection in IM-resistant CML cells. The results of the present study showed that dysregulated miR-153-3p may target Bcl-2 to promote the development of IM resistance and attenuate IM-induced apoptosis in CML. Therefore, miR-153-3p upregulation combined with IM treatment may serve as a promising therapeutic strategy for patients with low sensitivity.

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Availability of data and material

The datasets used and/or analyzed in the current study are available from the corresponding author on reasonable request.

References

  1. Branford S, Yeung DT, Parker WT, et al. Prognosis for patients with CML and %3e 10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood. 2014;124:511–8.

    CAS  PubMed  Article  Google Scholar 

  2. Druker BJ, O'Brien SG, Jorge C, Jerald R. Chronic myelogenous leukemia. Curr Opin Oncol. 2001;13:3.

    PubMed  Article  Google Scholar 

  3. Ruibao R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5:172–83.

    Article  Google Scholar 

  4. Moraes GND, Souza PS, Costas FCDF, Vasconcelos FC, Maia RC. The Interface between BCR-ABL-dependent and -independent resistance signaling pathways in chronic myeloid leukemia. Leukemia Res Treatment. 2012;2012:671702.

    Google Scholar 

  5. Mollaei H, Safaralizadeh R, Rostami Z. MicroRNA replacement therapy in cancer. J Cell Physiol. 2019;234:12369–84.

    CAS  PubMed  Article  Google Scholar 

  6. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–27.

    CAS  PubMed  Article  Google Scholar 

  7. Zhou J, Xie M, Shi Y, et al. MicroRNA-153 functions as a tumor suppressor by targeting SET7 and ZEB2 in ovarian cancer cells. Oncol Rep. 2015;34:111.

    CAS  PubMed  Article  Google Scholar 

  8. Cui Z, Luo Z, Lin Z, et al. Long non-coding RNA TTN-AS1 facilitates tumorigenesis of papillary thyroid cancer through modulating the miR-153-3p/ZNRF2 axis. J Gene Med. 2019;21:e3083.

    PubMed  Article  Google Scholar 

  9. Luan W, Shi Y, Zhou Z, et al. circRNA_0084043 promote malignant melanoma progression via miR-153-3p/Snail axis. Biochem Biophys Res Commun. 2018;502:22–9.

    CAS  PubMed  Article  Google Scholar 

  10. Jiang J, Liu Y, Zhao Y, Tian F, Wang G. miR-153-3p suppresses inhibitor of growth protein 2 expression to function as tumor suppressor in acute lymphoblastic leukemia. Technol Cancer Res Treatment. 2019;18:1533033819852990.

    CAS  Article  Google Scholar 

  11. Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science. 2004;306:990–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Ankit K, Umesh Kumar S, Anurag C. Targeting autophagy to overcome drug resistance in cancer therapy. Future Med Chem. 2015;7:1535–42.

    Article  Google Scholar 

  13. Takahashi Y, Coppola D, Matsushita N, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol. 2007;9:1142–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Zhu J, Li Y, Huang C, Huang H. Abstract 3310: Atg7 overexpression promotes bladder cancer invasion via autophagic removal of AUF1 protein and subsequently increased RhoGDI2 mRNA stability in vitro and in vivo. Can Res. 2017;77:3310–410.

    Google Scholar 

  15. Rohatgi RA, Shaw LM. An autophagy-independent function for Beclin 1 in cancer. Mol Cell Oncol. 2016;3(1):e1030539.

    PubMed  Article  Google Scholar 

  16. Alexander Scarth W, Monika M, Anna KS. Autophagy in the pathogenesis of myelodysplastic syndrome and acute myeloid leukemia. Cell Cycle. 2011;10:1719–25.

    Article  Google Scholar 

  17. Crowley LC, Elzinga BM, O'Sullivan GC, Mckenna SL. Autophagy induction by Bcr-Abl-expressing cells facilitates their recovery from a targeted or nontargeted treatment. Am J Hematol. 2011;86:38–47.

    CAS  PubMed  Article  Google Scholar 

  18. Cristian B, Maria Rosa L, Ashley H, et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Investig. 2009;119:1109–23.

    Article  Google Scholar 

  19. Beth L, Sangita S, Guido K. Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy. 2008;4:600–6.

    Article  Google Scholar 

  20. Manabu E, Ryungsa K, Kazuaki T, et al. Targeted therapy against Bcl-2-related proteins in breast cancer cells. Breast Cancer Res. 2005;7:R940–R952952.

    Article  Google Scholar 

  21. Lin TY, Chen KC, Liu HJ, et al. MicroRNA-1301-mediated RanGAP1 downregulation induces BCR-ABL nuclear entrapment to enhance imatinib efficacy in chronic myeloid leukemia cells. PLoS ONE. 2016;11:e0156260.

    PubMed  PubMed Central  Article  Google Scholar 

  22. Flis S, Chojnacki T. Chronic myelogenous leukemia, a still unsolved problem: pitfalls and new therapeutic possibilities. Drug Des Devel Ther. 2019;13:825–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Zhu X, Lin Z, Du J, et al. MicroRNA-320a acts as a tumor suppressor by targeting BCR/ABL oncogene in chronic myeloid leukemia. Sci Rep. 2015;5:12460.

    CAS  Article  Google Scholar 

  24. Tanida I, Ueno T, Kominami E. LC3 and autophagy. Methods Mol Biol. 2008;445:77–88.

    CAS  PubMed  Article  Google Scholar 

  25. Jabbour EJ, Cortes JE, Kantarjian HM. Resistance to tyrosine kinase inhibition therapy for chronic myelogenous leukemia: a clinical perspective and emerging treatment options. Clin Lymphoma Myeloma Leukemia. 2013;13:515–29.

    CAS  Article  Google Scholar 

  26. Lu Y, Liu LL, Liu SS, et al. Celecoxib suppresses autophagy and enhances cytotoxicity of imatinib in imatinib-resistant chronic myeloid leukemia cells. J Transl Med. 2016;14:270.

    PubMed  PubMed Central  Article  Google Scholar 

  27. Testa U, Riccioni R. Deregulation of apoptosis in acute myeloid leukemia. Haematologica. 2007;92:81.

    CAS  PubMed  Article  Google Scholar 

  28. Colin J, Gaumer S, Guenal I, Mignotte B. Mitochondria, Bcl-2 family proteins and apoptosomes: of worms, flies and men. Front Biosci. 2008;14:4127–37.

    Google Scholar 

  29. Chiang W-C, Wei Y, Kuo Y-C, et al. High-throughput screens to identify autophagy inducers that function by disrupting Beclin 1/Bcl-2 binding. ACS Chem Biol. 2018;13:2247–60

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Sun D, Mu Y, Piao H. MicroRNA-153-3p enhances cell radiosensitivity by targeting BCL2 in human glioma. Biol Res. 2018;51:56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Funding

This work was supported by the scientific and innovative strategic special fund of Guangdong province (2018A030310299), doctor initiating scientific project of The Third Affiliated Hospital of Guangzhou Medical University (2017B07), and elite personnel project of The Third Affiliated Hospital of Guangzhou Medical University (2018001).

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Authors

Contributions

Z-YL and Y-LL designed the research. Y-LL, Z-YL, J-MT, X-YC and BL performed the experiments, analyzed the data, and wrote the paper. G-HL performed the cell culture experiments. QQ collected the data and performed the statistical analyses.

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Correspondence to Zi-Yuan Lu.

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The authors declare that they have no conflict of interest.

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All human blood samples investigated in this study were in accordance with the ethical standards of the Ethics Committee of The Third Affiliated Hospital of Guangzhou Medical University, and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual sample donor included in the study.

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All authors have read and approved the publication of this paper.

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Li, YL., Tang, JM., Chen, XY. et al. MicroRNA-153-3p enhances the sensitivity of chronic myeloid leukemia cells to imatinib by inhibiting B-cell lymphoma-2-mediated autophagy. Human Cell 33, 610–618 (2020). https://doi.org/10.1007/s13577-020-00367-1

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  • DOI: https://doi.org/10.1007/s13577-020-00367-1

Keywords

  • miR-153-3p
  • Bcl-2
  • Imatinib
  • Autophagy
  • Chronic myeloid leukemia