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miRNA-21 regulates arsenic-induced anti-leukemia activity in myelogenous cell lines

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Abstract

MicroRNAs (miRNAs) are endogenous small noncoding RNA molecules involved in modulation of cellular sensitivity to anti-cancer drugs. miRNA-21 (miR-21), one of the most prominent miRNAs in the genesis and progression of many human cancers, has been rarely characterized in myelogenous leukemia. Arsenic trioxide (ATO) was successfully used in the treatment of acute promyelocytic leukemia (APL) etc. However, cytotoxicity or insensitivity is a major concern in the successful treatment of leukemia. Here, we used a specific precursor miRNA-21 (pre-miR-21) or anti-miRNA-21 oligonucleotide (AMO-miR-21) to study sensitivity of HL60 and K562 cells to ATO. Cell viability and cell cycle were evaluated by MTT assay and PI assay using flow cytometry, respectively. Levels of miR-21 and its target PDCD4 were quantified by real-time PCR and/or western blot. AMO-miR-21 or ATO alone led to growth inhibition, apoptosis and G1 phase arrest of cell cycle. Apoptotic cells were confirmed morphologically with Hoechst staining. Moreover, there was somewhat synergistic effect of AMO-miR-21 and ATO in growth inhibition and apoptosis promotion. Meanwhile, enforced pre-miR-21 expression increased resistance to ATO, nevertheless not affecting cell growth alone. Dual-luciferase reporter vector containing two tandem PDCD4 3′ UTR validated that PDCD4 was directly up-regulated by miR-21. Therefore, miRNA-21 by targeting PDCD4 may play a functional role in modulating ATO-induced cell death, and strategy using AMO-miR-21 and its combination with ATO may be useful as a myelogenous leukemia therapy.

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References

  1. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.

    Article  PubMed  CAS  Google Scholar 

  2. He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5:522–31.

    Article  PubMed  CAS  Google Scholar 

  3. Yu ZB, Jian ZF, Shen SH. Global analysis of microRNA target gene expression reveals that miRNA targets are lower expressed in mature mouse and Drosophila tissues than in the embryos. Nucleic Acids Res. 2007;35:152–64.

    Article  PubMed  CAS  Google Scholar 

  4. Griffiths-Jones S, Grocock RJ, van Dongen S, et al. miRBase: MicroRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 2006;34:D140–4.

    Article  PubMed  CAS  Google Scholar 

  5. Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–5.

    Article  PubMed  CAS  Google Scholar 

  6. Blower PE, Chung JH, Verducci JS. MicroRNAs modulate the chemosensitivity of tumor cells. Mol Cancer Ther. 2008;7:1–9.

    Article  PubMed  CAS  Google Scholar 

  7. Salerno E, Scaglione BJ, Coffman FD, Brown BD, Baccarini A, Fernandes H, et al. Correcting miR-15a/16 genetic defect in New Zealand Black mouse model of CLL enhances drug sensitivity. Mol Cancer Ther. 2009;8(9):268–92.

    Article  Google Scholar 

  8. Zhu H, Wu H, Liu X, Evans BR, Medina DJ. Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells. Biochem Pharmacol. 2008;76:582–8.

    Article  PubMed  CAS  Google Scholar 

  9. Boren T, Xiong Y, Hakam A, Wenham R, Apte S, Chan G, et al. MicroRNAs and their target messenger RNAs associated with ovarian cancer response to chemotherapy. Gynecol Oncol. 2009;113(2):249–55.

    Article  PubMed  CAS  Google Scholar 

  10. Lu Z, Liu M, Stribinskis V. MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene. 2008;27:4373–9.

    Article  PubMed  CAS  Google Scholar 

  11. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27:2128–36.

    Article  PubMed  CAS  Google Scholar 

  12. Li SZ. The compendium of materia medica. Beijing: People’s Medical Publishing House; 1982 (originally published in the Ming Dynasty of China, 1578).

  13. Aronson SM. Arsenic and old myths. R I Med. 1994;77:233–4.

    PubMed  CAS  Google Scholar 

  14. Sun HD, Ma L, Hu XC, Zhang TD. Ai-lin 1 treated 32 cases of acute promyelocytic leukemia. Chin J Integr Chin West Med. 1992;12:170–1.

    Google Scholar 

  15. Shen ZX, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL). II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:3354–60.

    PubMed  CAS  Google Scholar 

  16. Niu C, Yan H, Yu T, Sun HP, Liu JX, Li XS, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999;94:3315–24.

    PubMed  CAS  Google Scholar 

  17. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–60.

    PubMed  CAS  Google Scholar 

  18. Zhang QY, Mao JH, Liu P, Huang QH, Lu J, Xie YY, et al. A systems biology understanding of the synergistic effects of arsenic sulfide and Imatinib in BCR/ABL-associated leukemia. Proc Natl Acad Sci USA. 2009;106(9):3378–83.

    Article  PubMed  CAS  Google Scholar 

  19. Yin T, Wu YL, Sun HP, Sun GL, Du YZ, Wang KK, et al. Combined effects of As4S4 and imatinib on chronic myeloid leukemia cells and BCR-ABL oncoprotein. Blood. 2004;104(13):4219–25.

    Article  PubMed  CAS  Google Scholar 

  20. Chen Z, Chen GQ, Shen ZX, Sun GL, Tong JH, Wang ZY, et al. Expanding the use of arsenic trioxide: leukemias and beyond. Semin Hematol. 2002;39(2 Suppl 1):22–6. (Review).

    Article  PubMed  CAS  Google Scholar 

  21. Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA. 2009;106(9):3342–7.

    Article  PubMed  CAS  Google Scholar 

  22. Mathews V, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006;107:2627–32.

    Article  PubMed  CAS  Google Scholar 

  23. Ghavamzadeh A, et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol. 2006;17:131–4.

    Article  PubMed  CAS  Google Scholar 

  24. Gu S, Jin L, Zhang F, Sarnow P, Kay MA. Biological basis for restriction of microRNA targets to the 3′ untranslated region in mammalian mRNAs. Nat Struct Mol Biol. 2009;16(2):144–50. (Epub 2009 Feb 1).

    Article  PubMed  CAS  Google Scholar 

  25. Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA targets. Cell. 2003;115:787–98.

    Article  PubMed  CAS  Google Scholar 

  26. Manikandan J, Aarthi JJ, Kumar SD, Pushparaj PN. Oncomirs: the potential role of non-coding microRNAs in understanding cancer. Bioinformation. 2008;2:330–4.

    PubMed  Google Scholar 

  27. Esquela-Kerscher A, Slack FJ. Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.

    Article  PubMed  CAS  Google Scholar 

  28. Esau CC. Inhibition of microRNA with antisense oligonucleotides. Methods. 2008;44:55–60.

    Article  PubMed  CAS  Google Scholar 

  29. Cheng AM, Byrom MW, Shelton J. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 2005;33:1290–7.

    Article  PubMed  CAS  Google Scholar 

  30. Weiler J, Hunziker J, Hall J. Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease? Gene Ther. 2005;13:496–502.

    Article  Google Scholar 

  31. Lankat-Buttgereit B, Göke R. The tumour suppressor Pdcd4: recent advances in the elucidation of function and regulation. Biol Cell. 2009;101(6):309–17.

    Article  PubMed  CAS  Google Scholar 

  32. Yekta S, Shih IH, Bartel DP. MicroRNA-directed cleavage of HOXB8 mRNA. Science. 2004;304:594–6.

    Article  PubMed  CAS  Google Scholar 

  33. Bagga S, Bracht J, Hunter S, Massirer K, Holtz J, Eachus R, et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell. 2005;122:553–63.

    Article  PubMed  CAS  Google Scholar 

  34. Chen CY, Zheng D, Xia Z, Shyu AB. Ago-TNRC6 triggers microRNA-mediated decay by promoting two deadenylation steps. Nat Struct Mol Biol. 2009;16(11):1160–6. (Epub 2009 Oct 18).

    Article  PubMed  CAS  Google Scholar 

  35. Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, et al. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem. 2008;283:1026–33.

    Article  PubMed  CAS  Google Scholar 

  36. Fraser M, Leung BM, Yan X, Dan HC, Cheng JQ, Tsang BK. Tsang. p53 is a determinant of X-linked inhibitor of apoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells. Cancer Res. 2003;63:7081–8.

    PubMed  CAS  Google Scholar 

  37. Fraser M, Leung B, Jahani-Asl A, Yan X, Thompson WE, Tsang BK. Chemoresistance in human ovarian cancer: the role of apoptotic regulators. Reprod Biol Endocrinol. 2003;1:66.

    Article  PubMed  Google Scholar 

  38. Li J, Huang H, Sun L, Yang M, Pan C, Chen W, et al. MiR-21 indicates poor prognosis in tongue squamous cell carcinomas as an apoptosis inhibitor. Clin Cancer Res. 2009;15(12):3998–4008. (Epub 2009 Jun 9).

    Article  PubMed  CAS  Google Scholar 

  39. Krichevsky AM, Gabriely G. miR-21: a small multi-faceted RNA. J Cell Mol Med. 2009;13(1):39–53. (Review).

    Article  PubMed  CAS  Google Scholar 

  40. Selcuklu SD, Donoghue MT, Spillane C. miR-21 as a key regulator of oncogenic processes. Biochem Soc Trans. 2009;37(Pt 4):918–25. (Review).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Supported by grants from Guangdong Administration of Traditional Chinese Medicine Research Project (2008098), The Natural Science Foundation of Guang Dong Province (No. 5300488), Science and Technology Plan Projects of Guang Dong Province (No. 2006B35502010, No. 2005B33101005) and National Natural Science Foundation of China (No. 30800486).

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No competing interests exist among authors.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western huangpu avenue, 510632, Guangzhou, China

    Jingyi Gu, Xuejiao Zhu, Yumin Li, Haiyan Hu & Jia Fei

  2. Department of Clinical Medicine, Medical College of Jinan University, Guangzhou, China

    Dawei Dong, Junlin Yao, Chunyan Lin & Kangkang Huang

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  1. Jingyi Gu
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  2. Xuejiao Zhu
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  3. Yumin Li
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  4. Dawei Dong
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  6. Chunyan Lin
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  7. Kangkang Huang
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  8. Haiyan Hu
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  9. Jia Fei
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Correspondence to Haiyan Hu or Jia Fei.

Additional information

Jingyi Gu, Xuejiao Zhu and Yumin Li contributed equally to this study.

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Gu, J., Zhu, X., Li, Y. et al. miRNA-21 regulates arsenic-induced anti-leukemia activity in myelogenous cell lines. Med Oncol 28, 211–218 (2011). https://doi.org/10.1007/s12032-009-9413-7

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  • DOI: https://doi.org/10.1007/s12032-009-9413-7

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