Synergistic regulatory effects of microRNAs on brain glioma cells

Zhao,Yilei; Cui,Xiaomeng; Zhu,Wenliang; Chen,Xin; Shen,Chen; Liu,Zhendong; Yang,Guang; Liu,Yaohua; Zhao,Shiguang

doi:10.3892/mmr.2017.6709

Synergistic regulatory effects of microRNAs on brain glioma cells

Authors:
- Yilei Zhao
- Xiaomeng Cui
- Wenliang Zhu
- Xin Chen
- Chen Shen
- Zhendong Liu
- Guang Yang
- Yaohua Liu
- Shiguang Zhao
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Affiliations: Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Institute of Measurement-Control Technology and Communications Engineering, Harbin University of Science and Technology, Harbin, Heilongjiang 150010, P.R. China, Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China, Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: June 7, 2017 https://doi.org/10.3892/mmr.2017.6709
Pages: 1409-1416

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Abstract

Glioma is among the most common types of cancer of the central nervous system and is difficult to cure. Due to the lack of glioma-specific treatments, patients with glioma exhibit high mortality rates. MicroRNAs (miRNAs) participate in the pathogenesis of glioma, and upregulation of specific miRNAs promotes cell proliferation, whereas apoptosis‑inducing miRNAs are markedly downregulated in the context of glioma. Therefore, miRNAs may be important contributors to the pathogenesis of glioma. In the present study, nine miRNAs were investigated as miRNA‑miRNA pairs, and the measured cell viabilities were consistent with the results of synergy predictions. Extensive synergy occurred among upregulated miRNAs in U87 cells, whereas downregulated miRNAs rarely exhibited synergism. Treatment with an miRNA‑miRNA pair exhibiting strong synergy increased the inhibitory effects of these miRNAs on tumor cells, and the combined inhibitory effects were increased compared with the sum of the individual inhibitory effects of each miRNA. Using cell viability assays, TUNEL staining, and flow cytometry, the present study demonstrates that cotransfection with miR‑20a and miR‑21inhibitors resulted in the highest synergistic effect on the promotion of apoptosis in U87 cells. The results of the present study provide important insights into the potential use of miRNAs in the treatment of glioma.

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1	Gladson CL, Prayson RA and Liu WM: The pathobiology of glioma tumors. Annu Rev Pathol. 5:33–50. 2010. View Article : Google Scholar : PubMed/NCBI
2	Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, Stroup NE, Kruchko C and Barnholtz-Sloan JS: CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol. 15 Suppl 2:ii1–ii56. 2013. View Article : Google Scholar : PubMed/NCBI
3	Morgan LL: The epidemiology of glioma in adults: A ‘state of the science’ review. Neuro Oncol. 17:623–624. 2015. View Article : Google Scholar : PubMed/NCBI
4	Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P and Ellison DW: The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131:803–820. 2016. View Article : Google Scholar : PubMed/NCBI
5	Hervey-Jumper SL and Berger MS: Maximizing safe resection of low- and high-grade glioma. J Neuro Oncol. 130:pp269–282. 2016. View Article : Google Scholar
6	Stavrovskaya AA, Shushanov SS and Rybalkina EY: Problems of glioblastoma multiforme drug resistance. Biochemistry (Mosc). 81:91–100. 2016. View Article : Google Scholar : PubMed/NCBI
7	Zhang C, Li C, Li J, Han J, Shang D, Zhang Y, Zhang W, Yao Q, Han L, Xu Y, et al: Identification of miRNA-mediated core gene module for glioma patient prediction by integrating high-throughput miRNA, mRNA expression and pathway structure. PLoS One. 9:e969082014. View Article : Google Scholar : PubMed/NCBI
8	Adlakha YK and Saini N: Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128. Mol Cancer. 13:332014. View Article : Google Scholar : PubMed/NCBI
9	Onishi M, Ichikawa T, Kurozumi K and Date I: Angiogenesis and invasion in glioma. Brain Tumor Patho. 28:pp13–24. 2011. View Article : Google Scholar
10	Gaur AB, Holbeck SL, Colburn NH and Israel MA: Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo. Neuro Oncol. 13:580–590. 2011. View Article : Google Scholar : PubMed/NCBI
11	Li Y, Zhao S, Zhen Y, Li Q, Teng L, Asai A and Kawamoto K: A miR-21 inhibitor enhances apoptosis and reduces G(2)-M accumulation induced by ionizing radiation in human glioblastoma U251 cells. Brain Tumor Pathol. 28:209–214. 2011. View Article : Google Scholar : PubMed/NCBI
12	Zhang C, Zhang J, Hao J, Shi Z, Wang Y, Han L, Yu S, You Y, Jiang T, Wang J, et al: High level of miR-221/222 confers increased cell invasion and poor prognosis in glioma. J Transl Med. 10:e1192012. View Article : Google Scholar
13	Ernst A, Campos B, Meier J, Devens F, Liesenberg F, Wolter M, Reifenberger G, Herold-Mende C, Lichter P and Radlwimmer B: De-repression of CTGF via the miR-17-92 cluster upon differentiation of human glioblastoma spheroid cultures. Oncogene. 29:3411–3422. 2010. View Article : Google Scholar : PubMed/NCBI
14	Costa PM, Cardoso AL, Mano M and de Lima MC: MicroRNAs in glioblastoma: Role in pathogenesis and opportunities for targeted therapies. CNS Neurol Disord Drug Targets. 14:222–238. 2015. View Article : Google Scholar : PubMed/NCBI
15	Wu DG, Wang YY, Fan LG, Luo H, Han B, Sun LH, Wang XF, Zhang JX, Cao L, Wang XR, et al: MicroRNA-7 regulates glioblastoma cell invasion via targeting focal adhesion kinase expression. Chin Med J (Engl). 124:2616–2621. 2011.PubMed/NCBI
16	Chen G, Zhu W, Shi D, Lv L, Zhang C, Liu P and Hu W: MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2. Oncol Rep. 23:997–1003. 2010.PubMed/NCBI
17	Gabriely G, Wurdinger T, Kesari S, Esau CC, Burchard J, Linsley PS and Krichevsky AM: MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol. 28:5369–5380. 2008. View Article : Google Scholar : PubMed/NCBI
18	Xu J, Li CX, Li YS, Lv JY, Ma Y, Shao TT, Xu LD, Wang YY, Du L, Zhang YP, et al: MiRNA-miRNA synergistic network: Construction via co-regulating functional modules and disease miRNA topological features. Nucleic Acids Res. 39:825–836. 2011. View Article : Google Scholar : PubMed/NCBI
19	Hu S, Huang M, Nguyen PK, Gong Y, Li Z, Jia F, Lan F, Liu J, Nag D, Robbins RC and Wu JC: Novel microRNA prosurvival cocktail for improving engraftment and function of cardiac progenitor cell transplantation. Circulation. 124 11 Suppl:S27–S34. 2011. View Article : Google Scholar : PubMed/NCBI
20	Zhu W, Zhao Y, Xu Y, Sun Y, Wang Z, Yuan W and Du Z: Dissection of protein interactomics highlights microRNA synergy. PLoS One. 8:e633422013. View Article : Google Scholar : PubMed/NCBI
21	Singh S, Narang AS and Mahato RI: Subcellular fate and off-target effects of siRNA, shRNA, and miRNA. Pharm Res. 28:2996–3015. 2011. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Zhang Y, Dutta A and Abounader R: The role of microRNAs in glioma initiation and progression. Front Biosci (Landmark Ed). 17:700–712. 2012. View Article : Google Scholar : PubMed/NCBI
24	Codo P, Weller M, Meister G, Szabo E, Steinle A, Wolter M, Reifenberger G and Roth P: MicroRNA mediated down-regulation of NKG2D ligands contributes to glioma immune escape. Oncotarget. 5:7651–7662. 2014. View Article : Google Scholar : PubMed/NCBI
25	Visani M, de Biase D, Marucci G, Cerasoli S, Nigrisoli E, Reggiani ML Bacchi, Albani F, Baruzzi A and Pession A; PERNO study group, : Expression of 19 microRNAs in glioblastoma and comparison with other brain neoplasia of grades I–III. Mol Oncol. 8:417–430. 2014. View Article : Google Scholar : PubMed/NCBI
26	Feng SY, Dong CG, Wu K, Wang XG, Qiao J and Shao JF: Lentiviral expression of anti-microRNAs targeting miR-27a inhibits proliferation and invasiveness of U87 glioma cells. Mol Med Rep. 6:275–281. 2012.PubMed/NCBI
27	Shi R, Wang PY, Li XY, Chen JX, Li Y, Zhang XZ, Zhang CG, Jiang T, Li WB, Ding W and Cheng SJ: Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumor recurrence of glioma patients. Oncotarget. 6:26971–26981. 2015. View Article : Google Scholar : PubMed/NCBI
28	Gwak HS, Kim TH, Jo GH, Kim YJ, Kwak HJ, Kim JH, Yin J, Yoo H, Lee SH and Park JB: Silencing of microRNA-21 confers radio-sensitivity through inhibition of the PI3K/AKT pathway and enhancing autophagy in malignant glioma cell lines. PLoS One. 7:e474492012. View Article : Google Scholar : PubMed/NCBI
29	Han L, Yue X, Zhou X, Lan FM, You G, Zhang W, Zhang KL, Zhang CZ, Cheng JQ, Yu SZ, et al: MicroRNA-21 expression is regulated by β-catenin/STAT3 pathway and promotes glioma cell invasion by direct targeting RECK. CNS Neurosci Ther. 18:573–583. 2012. View Article : Google Scholar : PubMed/NCBI
30	Yao X, Li W, Wang Y, Ding Z, Hou W, Zeng M, Deng G, Zhang J and Yang H: Expression of hsa-miR-20a in human glioma tissues and its effect on the proliferation of human glioma cells in vitro. Nan Fang Yi Ke Da Xue Xue Bao. 32:198–201. 2012.(In Chinese). PubMed/NCBI
31	Kasinski AL, Kelnar K, Stahlhut C, Orellana E, Zhao J, Shimer E, Dysart S, Chen X, Bader AG and Slack FJ: A combinatorial microRNA therapeutics approach to suppressing non-small cell lung cancer. Oncogene. 34:3547–3555. 2015. View Article : Google Scholar : PubMed/NCBI
32	Stahlhut C and Slack FJ: Combinatorial action of MicroRNAs let-7 and miR-34 Effectively synergizes with erlotinib to suppress non-small cell lung cancer cell proliferation. Cell Cycle. 14:2171–2180. 2015. View Article : Google Scholar : PubMed/NCBI
33	Devulapally R, Sekar NM, Sekar TV, Foygel K, Massoud TF, Willmann JK and Paulmurugan R: Polymer nanoparticles mediated codelivery of antimiR-10b and antimiR-21 for achieving triple negative breast cancer therapy. ACS Nano. 9:2290–2302. 2015. View Article : Google Scholar : PubMed/NCBI
34	Jin H, Yu Y, Chrisler WB, Xiong Y, Hu D and Lei C: Delivery of MicroRNA-10b with polylysine nanoparticles for inhibition of breast cancer cell wound healing. Breast Cancer (Auckl). 6:9–19. 2012.PubMed/NCBI
35	Fernandez-Fernandez A, Manchanda R and McGoron AJ: Theranostic applications of nanomaterials in cancer: Drug delivery, image-guided therapy, and multifunctional platforms. Appl Biochem Biotechnol. 165:1628–1651. 2011. View Article : Google Scholar : PubMed/NCBI