Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Therapeutic effects of oligo-single-stranded DNA mimicking of hsa-miR-15a-5p on multiple myeloma

Abstract

Despite the fact that a few novel agents improve the outcome of patients, MM remains incurable. Hence, developing a novel treatment strategy may prove to be promising for the clinical management of MM. Noncoding small RNAs, a cluster of RNAs that do not encode functional proteins, have been underlined that play a pivotal role in the pathogenesis of MM. Our previous study indicated that miR-15a acted as a tumor suppressor, which inhibited the cell proliferation and promoted the apoptosis of MM cells. The level of miR-15a was downregulated in MM cells and correlated with inferior outcome of MM patients. In the present study, we first developed an oligo-single-stranded DNA mimicking the sequence of hsa-miR-15a-5p (OMM-15a) and modified with locked nucleic acid (LNA-15a) to evaluate its anti-MM effects. Our results indicated that the LNA-15a presented an exciting anti-MM effect that showed notable cell growth suppression and apoptosis promotion in MM and other cancer cell lines through downregulating the expression level of target genes BCL-2, VEGF-A, and PHF19. Moreover, LNA-15a treatment significantly improved the anti-MM activity of bortezomib with the synergism effect in OCI-My5 MM cells. In our in vivo study, LNA-15a treatment significantly suppressed the tumor growth, and prolonged the survival of mice compared with the control group. However, our results indicated that the native form of oligo-single-stranded DNA mimic of hsa-miR-15a-5p (OMM-15a) without any modification had no effective inhibition on cell growth, even after increasing the dosage of OMM-15a in the treatment. Altogether, our finding provides the preclinical rationale to support the oligo-single-stranded DNA mimic of hsa-miR-15a with LNA modification, which is a promising tool for the therapy of both MM and other tumors with miR-15a downregulation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Structure of pre-miR-15a, OMM-15a, and LNA-15a.
Fig. 2: LNA-15a suppressed tumor cell growth and induced apoptosis.
Fig. 3: LNA-15a suppressed the target gene of hsa-miR-15a-5p.
Fig. 4: In vitro activity of LNA-15a combined with BTZ.
Fig. 5: The anti-MM activity of LNA-15a in vivo.

References

  1. 1.

    Avet-Loiseau H. Introduction to a review series on advances in multiple myeloma. Blood 2019;133:621.

    CAS  PubMed  Google Scholar 

  2. 2.

    Roccaro AM, Sacco A, Thompson B, Leleu X, Azab AK, Azab F, et al. MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. Blood 2009;113:6669–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–22.

    CAS  PubMed  Google Scholar 

  4. 4.

    Hagedorn PH, Persson R, Funder ED, Albaek N, Diemer SL, Hansen DJ, et al. Locked nucleic acid: modality, diversity, and drug discovery. Drug Discov Today. 2018;23:101–14.

    CAS  PubMed  Google Scholar 

  5. 5.

    Chi X, Gatti P, Papoian T. Safety of antisense oligonucleotide and siRNA-based therapeutics. Drug Discov Today. 2017;22:823–33.

    CAS  PubMed  Google Scholar 

  6. 6.

    Geary RS, Norris D, Yu R, Bennett CF. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev. 2015;87:46–51.

    CAS  PubMed  Google Scholar 

  7. 7.

    Bennett CF. Therapeutic antisense oligonucleotides are coming of age. Annu Rev Med. 2019;70:307–21.

    CAS  PubMed  Google Scholar 

  8. 8.

    Benetatos L, Vartholomatos G. Deregulated microRNAs in multiple myeloma. Cancer 2012;118:878–87.

    CAS  PubMed  Google Scholar 

  9. 9.

    Liu T, Xu Z, Ou D, Liu J, Zhang J. The miR-15a/16 gene cluster in human cancer: a systematic review. J Cell Physiol. 2019;234:5496–506.

    CAS  PubMed  Google Scholar 

  10. 10.

    Hao M, Zang M, Wendlandt E, Xu Y, An G, Gong D, et al. Low serum miR-19a expression as a novel poor prognostic indicator in multiple myeloma. Int J Cancer. 2015;136:1835–44.

    CAS  PubMed  Google Scholar 

  11. 11.

    Li F, Xu Y, Deng S, Li Z, Zou D, Yi S, et al. MicroRNA-15a/16-1 cluster located at chromosome 13q14 is down-regulated but displays different expression pattern and prognostic significance in multiple myeloma. Oncotarget 2015;6:38270–82.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Li F, Hao M, Feng X, Zang M, Qin Y, Yi S, et al. Downregulated miR-33b is a novel predictor associated with disease progression and poor prognosis in multiple myeloma. Leuk Res 2015;39:793–9.

    PubMed  Google Scholar 

  13. 13.

    Hao M, Zhang L, An G, Meng H, Han Y, Xie Z, et al. Bone marrow stromal cells protect myeloma cells from bortezomib induced apoptosis by suppressing microRNA-15a expression. Leuk lymphoma. 2011;52:1787–94.

    CAS  PubMed  Google Scholar 

  14. 14.

    Hao M, Zhang L, An G, Sui W, Yu Z, Zou D, et al. Suppressing miRNA-15a/-16 expression by interleukin-6 enhances drug-resistance in myeloma cells. J Hematol Oncol. 2011;4:37.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Shi J, Fu Q, Yang P, Liu H, Ji L, Wang K. Downregulation of microRNA-15a-3p is correlated with clinical outcome and negatively regulates cancer proliferation and migration in human osteosarcoma. J Cell Biochem. 2018;119:1215–22.

    CAS  PubMed  Google Scholar 

  16. 16.

    Liu L, Wang D, Qiu Y, Dong H, Zhan X. Overexpression of microRNA-15 increases the chemosensitivity of colon cancer cells to 5-fluorouracil and oxaliplatin by inhibiting the nuclear factor-kappaB signalling pathway and inducing apoptosis. Exp Ther Med. 2018;15:2655–60.

    CAS  PubMed  Google Scholar 

  17. 17.

    Li G, Chong T, Xiang X, Yang J, Li H. Downregulation of microRNA-15a suppresses the proliferation and invasion of renal cell carcinoma via direct targeting of eIF4E. Oncol Rep 2017;38:1995–2002.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    He J. Knocking down MiR-15a expression promotes the occurrence and development and induces the EMT of NSCLC cells in vitro. Saudi J Biol Sci. 2017;24:1859–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Long J, Jiang C, Liu B, Fang S, Kuang M. MicroRNA-15a-5p suppresses cancer proliferation and division in human hepatocellular carcinoma by targeting BDNF. Tumour Biol. 2016;37:5821–8.

    CAS  PubMed  Google Scholar 

  20. 20.

    Alderman C, Sehlaoui A, Xiao Z, Yang Y. MicroRNA-15a inhibits the growth and invasiveness of malignant melanoma and directly targets on CDCA4 gene. Tumour Biol. 2016;37:13941–50.

    CAS  PubMed  Google Scholar 

  21. 21.

    Dwivedi SK, Mustafi SB, Mangala LS, Jiang D, Pradeep S, Rodriguez-Aguayo C, et al. Therapeutic evaluation of microRNA-15a and microRNA-16 in ovarian cancer. Oncotarget 2016;7:15093–104.

    PubMed  Google Scholar 

  22. 22.

    Hao M, Franqui-Machin R, Xu H, Shaughnessy J Jr., Barlogie B, Roodman D, et al. NEK2 induces osteoclast differentiation and bone destruction via heparanase in multiple myeloma. Leukemia 2017;31:1648–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Franqui-Machin R, Hao M, Bai H, Gu Z, Zhan X, Habelhah H, et al. Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma. J Clin Investig. 2018;128:2877–93.

    PubMed  Google Scholar 

  24. 24.

    Hao M, Barlogie B, Tricot G, Liu L, Qiu L, Shaughnessy JD Jr., et al. Gene expression profiling reveals aberrant T-cell marker expression on tumor cells of Waldenstrom’s macroglobulinemia. Clin Cancer Res. 2019;25:201–9.

    CAS  PubMed  Google Scholar 

  25. 25.

    Yang Y, Zhang X, Lin F, Xiong M, Fan D, Yuan X, et al. Bispecific CD3-HAC carried by E1A-engineered mesenchymal stromal cells against metastatic breast cancer by blocking PD-L1 and activating T cells. J Hematol Oncol. 2019;12:46.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Morelli E, Biamonte L, Federico C, Amodio N, Di Martino MT, Gallo Cantafio ME, et al. Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-mir-17-92. Blood. 2018;132:1050–1063.

  27. 27.

    Bozok Cetintas V, Tetik Vardarli A, Duzgun Z, Tezcanli Kaymaz B, Acikgoz E, Aktug H, et al. miR-15a enhances the anticancer effects of cisplatin in the resistant non-small cell lung cancer cells. Tumour Biol. 2016;37:1739–51.

    CAS  PubMed  Google Scholar 

  28. 28.

    Ibrahim AF, Weirauch U, Thomas M, Grunweller A, Hartmann RK, Aigner A. MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma. Cancer Res 2011;71:5214–24.

    CAS  PubMed  Google Scholar 

  29. 29.

    Trang P, Wiggins JF, Daige CL, Cho C, Omotola M, Brown D, et al. Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice. Mol Ther 2011;19:1116–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Kasinski AL, Slack FJ. miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma. Cancer Res 2012;72:5576–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Pecot CV, Rupaimoole R, Yang D, Akbani R, Ivan C, Lu C, et al. Tumour angiogenesis regulation by the miR-200 family. Nat Commun. 2013;4:2427.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Zhang L, Zhou L, Shi M, Kuang Y, Fang L. Downregulation of miRNA-15a and miRNA-16 promote tumor proliferation in multiple myeloma by increasing CABIN1 expression. Oncol Lett. 2018;15:1287–96.

    PubMed  Google Scholar 

  33. 33.

    Pekarsky Y, Balatti V, Croce CM. BCL2 and miR-15/16: from gene discovery to treatment. Cell Death Differ. 2018;25:21–26.

    CAS  PubMed  Google Scholar 

  34. 34.

    Sun CY, She XM, Qin Y, Chu ZB, Chen L, Ai LS, et al. miR-15a and miR-16 affect the angiogenesis of multiple myeloma by targeting VEGF. Carcinogenesis 2013;34:426–35.

    CAS  PubMed  Google Scholar 

  35. 35.

    Sambri I, Capasso R, Pucci P, Perna AF, Ingrosso D. The microRNA 15a/16-1 cluster down-regulates protein repair isoaspartyl methyltransferase in hepatoma cells: implications for apoptosis regulation. J Biol Chem. 2011;286:43690–700.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Utaijaratrasmi P, Vaeteewoottacharn K, Tsunematsu T, Jamjantra P, Wongkham S, Pairojkul C, et al. The microRNA-15a-PAI-2 axis in cholangiocarcinoma-associated fibroblasts promotes migration of cancer cells. Mol Cancer 2018;17:10.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Li P, Xie XB, Chen Q, Pang GL, Luo W, Tu JC, et al. MiRNA-15a mediates cell cycle arrest and potentiates apoptosis in breast cancer cells by targeting synuclein-gamma. Asian Pac J Cancer Prev 2014;15:6949–54.

    PubMed  Google Scholar 

  38. 38.

    Zhao K, Zhan R, Wu SQ, Huang HB, Xu ZZ, Niu WY. Growth inhibition of multiple myeloma cells caused by microRNA-15a and its mechanisms. Zhongguo shi Yan Xue Ye Xue Za Zhi. 2015;23:706–12.

    CAS  PubMed  Google Scholar 

  39. 39.

    Li Y, Zhang B, Li W, Wang L, Yan Z, Li H, et al. MiR-15a/16 regulates the growth of myeloma cells, angiogenesis and antitumor immunity by inhibiting Bcl-2, VEGF-A and IL-17 expression in multiple myeloma. Leuk Res 2016;49:73–9.

    CAS  PubMed  Google Scholar 

  40. 40.

    Wickstrom E. Oligodeoxynucleotide stability in subcellular extracts and culture media. J Biochem Biophys Methods. 1986;13:97–102.

    CAS  PubMed  Google Scholar 

  41. 41.

    Verma A. Recent advances in antisense oligonucleotide therapy in genetic neuromuscular diseases. Ann Indian Acad Neurol. 2018;21:3–8.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Laxton C, Brady K, Moschos S, Turnpenny P, Rawal J, Pryde DC, et al. Selection, optimization, and pharmacokinetic properties of a novel, potent antiviral locked nucleic acid-based antisense oligomer targeting hepatitis C virus internal ribosome entry site. Antimicrob Agents Chemother. 2011;55:3105–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Chari A, Martinez-Lopez J, Mateos MV, Blade J, Benboubker L, Oriol A, et al. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood 2019;134:421–31.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Lingling Cheng for helping in the in vivo study and Ning Ji for revising the paper.

Funding

This work was supported by the Natural Science Foundation of China (81570181 and 81400174 to MH and 81630007 to LQ); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences CAMS-2017-I2M-1-005, CAMS-2016-I2M-3-031, and CAMS-2017-I2M-1-015 (to MH and LQ); Tianjin Science and Technology Supporting Program (17JCYBJC27900 to MH), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018RC320012 to MH).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Yongrong Lai or Mu Hao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, Z., Liu, L., Du, C. et al. Therapeutic effects of oligo-single-stranded DNA mimicking of hsa-miR-15a-5p on multiple myeloma. Cancer Gene Ther 27, 869–877 (2020). https://doi.org/10.1038/s41417-020-0161-3

Download citation

Further reading

Search

Quick links