Downregulation of miR‑186 promotes the proliferation and drug resistance of glioblastoma cells by targeting Twist1

  • Authors:
    • Yifeng Xiong
    • Rensheng Chen
    • Lizhen Wang
    • Shanshan Wang
    • Yi Tu
    • Lei Zhu
    • Chunliang Wang
  • View Affiliations

  • Published online on: April 30, 2019     https://doi.org/10.3892/mmr.2019.10207
  • Pages: 5301-5308
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Temozolomide (TMZ) is widely used as a chemotherapeutic agent in the treatment of glioma; however, the development of drug resistance remains a major obstacle in the effective treatment of glioblastoma. Increasing evidence has indicated that microRNAs (miRs) are involved in the drug resistance of glioma; however, the role of miR‑186‑5p in the TMZ resistance of glioblastoma remains unknown. In the present study, the role of miR‑186‑5p in the resistance of glioblastoma to TMZ was investigated. mRNA and protein expression levels were detected via reverse transcription‑quantitative PCR and western blot analysis, respectively. It was determined that miR‑186‑5p was significantly downregulated in glioblastoma tissues and cell lines. Additionally, the expression of miR‑186‑5p was decreased, whereas that of Twist1 was upregulated during the development of drug resistance in glioma cells. The introduction of miR‑186 into glioblastoma cells via transfection decreased the proliferation and TMZ resistance of glioblastoma cells, as determined via 5‑ethynyl‑2'‑deoxyuridine and Cell Counting Kit‑8 assays, whereas the inhibition of miR‑186‑5p induced opposing effects. Furthermore, luciferase reporter and expression rescue assays revealed that miR‑186‑5p bound to the 3'‑untranslated region of Twist‑related protein 1 (Twist1). In conclusion, the present study demonstrated that downregulation of miR‑186‑5p may contribute to the proliferation and drug resistance of glioblastoma cells via the regulation of Twist1 expression. These results suggested that miR‑186‑5p may be a novel therapeutic target in the treatment of glioblastoma.

References

1 

Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL and Rich JN: Cancer stem cells in glioblastoma. Genes Dev. 29:1203–1217. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Kim SS, Harford JB, Pirollo KF and Chang EH: Effective treatment of glioblastoma requires crossing the blood-brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine. Biochem Biophys Res Commun. 468:485–489. 2015. View Article : Google Scholar : PubMed/NCBI

3 

Mirimanoff RO: High-grade gliomas: Reality and hopes. Chin J Cancer. 33:1–3. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Grauer OM, Wesseling P and Adema GJ: Immunotherapy of diffuse gliomas: Biological background, current status and future developments. Brain Pathol. 19:674–693. 2009. View Article : Google Scholar : PubMed/NCBI

5 

Patil SA, Hosni-Ahmed A, Jones TS, Patil R, Pfeffer LM and Miller DD: Novel approaches to glioma drug design and drug screening. Expert Opin Drug Discov. 8:1135–1151. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Lujambio A and Lowe SW: The microcosmos of cancer. Nature. 482:347–355. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Sarkar FH, Li Y, Wang Z, Kong D and Ali S: Implication of microRNAs in drug resistance for designing novel cancer therapy. Drug Resist Updat. 13:57–66. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Zhu X, Shen H, Yin X, Long L, Xie C, Liu Y, Hui L, Lin X, Fang Y, Cao Y, et al: miR-186 regulation of Twist1 and ovarian cancer sensitivity to cisplatin. Oncogene. 35:323–332. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Erdmann K, Kaulke K, Thomae C, Huebner D, Sergon M, Froehner M, Wirth MP and Fuessel S: Elevated expression of prostate cancer-associated genes is linked to down-regulation of microRNAs. BMC Cancer. 14:822014. View Article : Google Scholar : PubMed/NCBI

11 

Cai J, Wu J, Zhang H, Fang L, Huang Y, Yang Y, Zhu X, Li R and Li M: miR-186 downregulation correlates with poor survival in lung adenocarcinoma, where it interferes with cell-cycle regulation. Cancer Res. 73:756–766. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A and Weinberg RA: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 117:927–939. 2004. View Article : Google Scholar : PubMed/NCBI

13 

Wang X, Ling MT, Guan XY, Tsao SW, Cheung HW, Lee DT and Wong YC: Identification of a novel function of TWIST, a bHLH protein, in the development of acquired taxol resistance in human cancer cells. Oncogene. 23:474–482. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH and Hannon GJ: Twist is a potential oncogene that inhibits apoptosis. Genes Dev. 13:2207–2217. 1999. View Article : Google Scholar : PubMed/NCBI

15 

Mikheeva SA, Mikheev AM, Petit A, Beyer R, Oxford RG, Khorasani L, Maxwell JP, Glackin CA, Wakimoto H, González-Herrero I, et al: TWIST1 promotes invasion through mesenchymal change in human glioblastoma. Mol Cancer. 9:1942010. View Article : Google Scholar : PubMed/NCBI

16 

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

17 

Lan J, Xue Y, Chen H, Zhao S, Wu Z, Fang J, Han C and Lou M: Hypoxia-induced miR-497 decreases glioma cell sensitivity to TMZ by inhibiting apoptosis. FEBS Lett. 588:3333–3339. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Jiang J, Wang W, Fang D, Jin X, Ding L and Sun X: MicroRNA186 targets IGF-1R and exerts tumor-suppressing functions in glioma. Mol Med Rep. 16:7821–7828. 2017. View Article : Google Scholar : PubMed/NCBI

19 

Myatt SS, Wang J, Monteiro LJ, Christian M, Ho KK, Fusi L, Dina RE, Brosens JJ, Ghaem-Maghami S and Lam EW: Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res. 70:367–377. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Goeppert B, Schmezer P, Dutruel C, Oakes C, Renner M, Breinig M, Warth A, Vogel MN, Mittelbronn M, Mehrabi A, et al: Down-regulation of tumor suppressor A kinase anchor protein 12 in human hepatocarcinogenesis by epigenetic mechanisms. Hepatology. 52:2023–2033. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Tan Z, Zhao J and Jiang Y: MiR-634 sensitizes glioma cells to temozolomide by targeting CYR61 through Raf-ERK signaling pathway. Cancer Med. 7:913–921. 2018. View Article : Google Scholar : PubMed/NCBI

22 

Li FF, Xing C, Wu LL and Xue F: MiR-205 enhances cisplatin sensitivity of glioma cells by targeting E2F1. Eur Rev Med Pharmacol Sci. 22:299–306. 2018.PubMed/NCBI

23 

Kim J, Yoon H, Chung DE, Brown JL, Belmonte KC and Kim J: miR-186 is decreased in aged brain and suppresses BACE1 expression. J Neurochem. 137:436–445. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Lei GS, Kline HL, Lee CH, Wilkes DS and Zhang C: Regulation of Collagen V expression and epithelial-mesenchymal transition by miR-185 and miR-186 during idiopathic pulmonary fibrosis. Am J Pathol. 186:2310–2316. 2016. View Article : Google Scholar : PubMed/NCBI

25 

Lee YH, Kim SY and Bae YS: Upregulation of miR-760 and miR-186 is associated with replicative senescence in human lung fibroblast cells. Mol Cells. 37:620–627. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Lee KE and Bar-Sagi D: Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells. Cancer Cell. 18:448–458. 2010. View Article : Google Scholar : PubMed/NCBI

27 

Beck B, Lapouge G, Rorive S, Drogat B, Desaedelaere K, Delafaille S, Dubois C, Salmon I, Willekens K, Marine JC and Blanpain C: Different levels of Twist1 regulate skin tumor initiation, stemness, and progression. Cell Stem Cell. 16:67–79. 2015. View Article : Google Scholar : PubMed/NCBI

28 

Ansieau S, Morel AP, Hinkal G, Bastid J and Puisieux A: TWISTing an embryonic transcription factor into an oncoprotein. Oncogene. 29:3173–3184. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Nordfors K, Haapasalo J, Makela K, Granberg KJ, Nykter M, Korja M, Paavonen T, Haapasalo H and Soini Y: Twist predicts poor outcome of patients with astrocytic glioma. J Clin Pathol. 68:905–912. 2015. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June 2019
Volume 19 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Xiong, Y., Chen, R., Wang, L., Wang, S., Tu, Y., Zhu, L., & Wang, C. (2019). Downregulation of miR‑186 promotes the proliferation and drug resistance of glioblastoma cells by targeting Twist1. Molecular Medicine Reports, 19, 5301-5308. https://doi.org/10.3892/mmr.2019.10207
MLA
Xiong, Y., Chen, R., Wang, L., Wang, S., Tu, Y., Zhu, L., Wang, C."Downregulation of miR‑186 promotes the proliferation and drug resistance of glioblastoma cells by targeting Twist1". Molecular Medicine Reports 19.6 (2019): 5301-5308.
Chicago
Xiong, Y., Chen, R., Wang, L., Wang, S., Tu, Y., Zhu, L., Wang, C."Downregulation of miR‑186 promotes the proliferation and drug resistance of glioblastoma cells by targeting Twist1". Molecular Medicine Reports 19, no. 6 (2019): 5301-5308. https://doi.org/10.3892/mmr.2019.10207