Tumor Biology

, Volume 36, Issue 11, pp 8943–8951 | Cite as

MicroRNA-219-5p exerts tumor suppressor function by targeting ROBO1 in glioblastoma

Research Article

Abstract

Previous studies have shown that miR-219-5p is dysregulated and exerts tumor-suppressive effects in cancer development and progression. However, the molecular function and mechanism of miR-219-5p in glioblastoma growth and invasion are still unclear. In the present study, we show that miR-219-5p was downregulated in a panel of glioma tissues with different grades and in all the human glioma cell lines examined. Ectopic expression of miR-219-5p inhibited proliferation and invasion and induced apoptosis in vitro, and xenograft formation in vivo. ROBO1 was found to be a direct target of miR-219-5p, and when overexpressed in miR-219-5p-expressing glioma cells, was able to restore proliferative and invasive ability. Finally, in vivo investigation confirmed that miR-219-5p was a tumor suppressor that regulated ROBO1 expression. Taken together, these studies demonstrate that miR-219-5p inhibited cancer cell growth and invasion by direct targeting ROBO1, implicating miR-219-5p as an attractive candidate for cancer therapy.

Keywords

Glioblastoma miR-219-5p ROBO1 Proliferation Invasion 

Notes

Conflicts of interest

None

References

  1. 1.
    Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol. 2005;109:93–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Schwartzbaum JA, Fisher JL, Aldape KD, Wrensch M. Epidemiology and molecular pathology of glioma. Nat Clin Pract Neurol. 2006;2:494–503.CrossRefPubMedGoogle Scholar
  3. 3.
    Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492–507.CrossRefPubMedGoogle Scholar
  5. 5.
    Glas M, Rath BH, Simon M, Reinartz R, Schramme A, Trageser D, et al. Residual tumor cells are unique cellular targets in glioblastoma. Ann Neurol. 2010;68:264–9.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.CrossRefPubMedGoogle Scholar
  7. 7.
    He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5:522–31.CrossRefPubMedGoogle Scholar
  8. 8.
    Eulalio A, Huntzinger E, Izaurralde E. Getting to the root of miRNA-mediated gene silencing. Cell. 2008;132:9–14.CrossRefPubMedGoogle Scholar
  9. 9.
    Liu Z, Liu Y, Li L, Xu Z, Bi B, Wang Y, et al. MiR-7-5p is frequently downregulated in glioblastoma microvasculature and inhibits vascular endothelial cell proliferation by targeting RAF1. Tumour Biol. 2014;35:10177–84.CrossRefPubMedGoogle Scholar
  10. 10.
    Wang F, Xiao W, Sun J, Han D, Zhu Y. MiRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing Akt phosphorylation in glioblastoma. Tumour Biol. 2014;35:8653–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65:6029–33.CrossRefPubMedGoogle Scholar
  12. 12.
    Tivnan A, Zhao J, Johns TG, Day BW, Stringer BW, Boyd AW, et al. The tumor suppressor microRNA, miR-124a, is regulated by epigenetic silencing and by the transcriptional factor, REST in glioblastoma. Tumour Biol. 2014;35:1459–65.CrossRefPubMedGoogle Scholar
  13. 13.
    Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, et al. MiR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008;6:14.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Conti A, Aguennouz M, La Torre D, Tomasello C, Cardali S, Angileri FF, et al. MiR-21 and 221 upregulation and miR-181b downregulation in human grade II-IV astrocytic tumors. J Neurooncol. 2009;93:325–32.CrossRefPubMedGoogle Scholar
  15. 15.
    Shi L, Cheng Z, Zhang J, Li R, Zhao P, Fu Z, et al. Hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells. Brain Res. 2008;1236:185–93.CrossRefPubMedGoogle Scholar
  16. 16.
    Rao SA, Santosh V, Somasundaram K. Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma. Mod Pathol. 2010;23:1404–17.CrossRefPubMedGoogle Scholar
  17. 17.
    Rao SA, Arimappamagan A, Pandey P, Santosh V, Hegde AS, Chandramouli BA, et al. MiR-219-5p inhibits receptor tyrosine kinase pathway by targeting EGFR in glioblastoma. PLoS One. 2013;8, e63164.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Huang N, Lin J, Ruan J, Su N, Qing R, Liu F, et al. MiR-219-5p inhibits hepatocellular carcinoma cell proliferation by targeting glypican-3. FEBS Lett. 2012;586:884–91.CrossRefPubMedGoogle Scholar
  19. 19.
    Huang C, Cai Z, Huang M, Mao C, Zhang Q, Lin Y, et al. MiR-219-5p modulates cell growth of papillary thyroid carcinoma by targeting estrogen receptor alpha. J Clin Endocrinol Metab. 2015;100:E204–13.CrossRefPubMedGoogle Scholar
  20. 20.
    Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.CrossRefPubMedGoogle Scholar
  21. 21.
    Novakova J, Slaby O, Vyzula R, Michalek J. MicroRNA involvement in glioblastoma pathogenesis. Biochem Biophys Res Commun. 2009;386:1–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Besse A, Sana J, Fadrus P, Slaby O. MicroRNAs involved in chemo- and radioresistance of high-grade gliomas. Tumour Biol. 2013;34:1969–78.CrossRefPubMedGoogle Scholar
  23. 23.
    Hu J, Jiang C, Ng HK, Pang JC, Tong CY, Chen S. Genome-wide allelotype study of primary glioblastoma multiforme. Chin Med J (Engl). 2003;116:577–83.Google Scholar
  24. 24.
    Dontula R, Dinasarapu A, Chetty C, Pannuru P, Herbert E, Ozer H, et al. MicroRNA 203 modulates glioma cell migration via Robo1/ERK/MMP-9 signaling. Genes Cancer. 2013;4:285–96.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Okuda H, Xing F, Pandey PR, Sharma S, Watabe M, Pai SK, et al. MiR-7 suppresses brain metastasis of breast cancer stem-like cells by modulating KLF4. Cancer Res. 2013;73:1434–44.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Di Leva G, Garofalo M, Croce CM. MicroRNAs in cancer. Annu Rev Pathol. 2014;9:287–314.CrossRefPubMedGoogle Scholar
  27. 27.
    Kidd T, Brose K, Mitchell KJ, Fetter RD, Tessier-Lavigne M, Goodman CS, et al. Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell. 1998;92:205–15.CrossRefPubMedGoogle Scholar
  28. 28.
    Hannula-Jouppi K, Kaminen-Ahola N, Taipale M, Eklund R, Nopola-Hemmi J, Kaariainen H, et al. The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia. PLoS Genet. 2005;1, e50.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Mascheretti S, Riva V, Giorda R, Beri S, Lanzoni LF, Cellino MR, et al. KIAA0319 and ROBO1: evidence on association with reading and pleiotropic effects on language and mathematics abilities in developmental dyslexia. J Hum Genet. 2014;59:189–97.CrossRefPubMedGoogle Scholar
  30. 30.
    Bates TC, Luciano M, Medland SE, Montgomery GW, Wright MJ, Martin NG. Genetic variance in a component of the language acquisition device: ROBO1 polymorphisms associated with phonological buffer deficits. Behav Genet. 2011;41:50–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Alajez NM, Lenarduzzi M, Ito E, Hui AB, Shi W, Bruce J, et al. MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway. Cancer Res. 2011;71:2381–91.CrossRefPubMedGoogle Scholar
  32. 32.
    Khusial PR, Vadla B, Krishnan H, Ramlall TF, Shen Y, Ichikawa H, et al. Src activates Abl to augment Robo1 expression in order to promote tumor cell migration. Oncotarget. 2010;1:198–209.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Xu Y, Li WL, Fu L, Gu F, Ma YJ. Slit2/Robo1 signaling in glioma migration and invasion. Neurosci Bull. 2010;26:474–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yongmei Jiang
    • 1
  • Lin Yin
    • 1
  • Huirong Jing
    • 1
  • Hui Zhang
    • 1
  1. 1.Department of Neurology, Second Affiliated HospitalDalian Medical UniversityDalianChina

Personalised recommendations