Therapeutic effects of oligo-single-stranded DNA mimicking of hsa-miR-15a-5p on multiple myeloma.
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
09
10
2019
accepted:
07
01
2020
revised:
21
12
2019
pubmed:
29
1
2020
medline:
22
12
2021
entrez:
29
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31988477
doi: 10.1038/s41417-020-0161-3
pii: 10.1038/s41417-020-0161-3
doi:
Substances chimiques
DNA, Single-Stranded
0
MIRN15 microRNA, human
0
MicroRNAs
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
869-877Références
Avet-Loiseau H. Introduction to a review series on advances in multiple myeloma. Blood 2019;133:621.
pubmed: 30587526
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.
pubmed: 19401561
pmcid: 2710922
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.
pubmed: 28209991
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.
pubmed: 28988994
Chi X, Gatti P, Papoian T. Safety of antisense oligonucleotide and siRNA-based therapeutics. Drug Discov Today. 2017;22:823–33.
pubmed: 28159625
Geary RS, Norris D, Yu R, Bennett CF. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev. 2015;87:46–51.
pubmed: 25666165
Bennett CF. Therapeutic antisense oligonucleotides are coming of age. Annu Rev Med. 2019;70:307–21.
pubmed: 30691367
Benetatos L, Vartholomatos G. Deregulated microRNAs in multiple myeloma. Cancer 2012;118:878–87.
pubmed: 21837684
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.
pubmed: 30246332
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.
pubmed: 25220540
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: 26516702
pmcid: 4741998
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: 25975752
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.
pubmed: 21534877
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.
pubmed: 21936961
pmcid: 3189173
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.
pubmed: 28722268
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.
pubmed: 29467857
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.
pubmed: 28849086
pmcid: 5652948
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.
pubmed: 29551936
pmcid: 5851900
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.
pubmed: 26581909
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.
pubmed: 27492455
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: 26918603
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.
pubmed: 28400617
pmcid: 5508075
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: 29863498
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.
pubmed: 30279229
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: 31023384
pmcid: 6482514
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.
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.
pubmed: 26314859
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.
pubmed: 21690566
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.
pubmed: 21427705
pmcid: 3129804
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.
pubmed: 22964582
pmcid: 3488137
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: 24018975
pmcid: 3904438
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: 29399181
Pekarsky Y, Balatti V, Croce CM. BCL2 and miR-15/16: from gene discovery to treatment. Cell Death Differ. 2018;25:21–26.
pubmed: 28984869
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.
pubmed: 23104180
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.
pubmed: 22033921
pmcid: 3243558
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: 29347950
pmcid: 5773154
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: 25169552
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.
pubmed: 26117022
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.
pubmed: 27596960
Wickstrom E. Oligodeoxynucleotide stability in subcellular extracts and culture media. J Biochem Biophys Methods. 1986;13:97–102.
pubmed: 3772027
Verma A. Recent advances in antisense oligonucleotide therapy in genetic neuromuscular diseases. Ann Indian Acad Neurol. 2018;21:3–8.
pubmed: 29720791
pmcid: 5909143
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.
pubmed: 21502629
pmcid: 3122463
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.
pubmed: 31113777
pmcid: 6676132