Abstract
It is suggested that microRNAs play important roles in the development of various cancers. Here, we showed that miR-137 is downregulated in glioblastoma (GBM) cell lines and that low levels of miR-137 are associated with a poor prognostic phenotype of GBM patients. Ectopic expression of miR-137 significantly inhibited GBM cell proliferation and angiogenesis. In addition, ectopic expression of miR-137 inhibited tumor growth and angiogenesis in a SCID mouse xenograft model. EZH2 was identified as a direct target of miR-137 by using luciferase reporter and Western blot assays, and EZH2 overexpression can rescue the inhibitory effect of miR-137 on cell proliferation and angiogenesis. Furthermore, tumor samples from GBM patients showed an inverse relationship between miR-137 and EZH2 levels. Our results suggest that miR-137 may serve as a biomarker in GBM, and the modulation of its activity may represent a novel therapeutic strategy for the treatment of GBM patients.
Similar content being viewed by others
References
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109. doi:10.1007/s00401-007-0243-4
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain T, Radiation Oncology G, National Cancer Institute of Canada Clinical Trials G (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466. doi:10.1016/S1470-2045(09)70025-7
Plasterk RH (2006) Micro RNAs in animal development. Cell 124:877–881. doi:10.1016/j.cell.2006.02.030
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297
Di Leva G, Garofalo M, Croce CM (2014) MicroRNAs in Cancer. Annu Rev Pathol 9:287–314. doi:10.1146/annurev-pathol-012513-104715
Moller HG, Rasmussen AP, Andersen HH, Johnsen KB, Henriksen M, Duroux M (2013) A systematic review of microRNA in glioblastoma multiforme: micro-modulators in the mesenchymal mode of migration and invasion. Mol Neurobiol 47:131–144. doi:10.1007/s12035-012-8349-7
Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vandenberg SR, Ginzinger DG, James CD, Costello JF, Bergers G, Weiss WA, Alvarez-Buylla A, Hodgson JG (2008) miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 6:14. doi:10.1186/1741-7015-6-14
Xie YK, Huo SF, Zhang G, Zhang F, Lian ZP, Tang XL, Jin C (2012) CDA-2 induces cell differentiation through suppressing Twist/SLUG signaling via miR-124 in glioma. J Neurooncol 110:179–186. doi:10.1007/s11060-012-0961-x
Zhang H, Qi M, Li S, Qi T, Mei H, Huang K, Zheng L, Tong Q (2012) microRNA-9 targets matrix metalloproteinase 14 to inhibit invasion, metastasis, and angiogenesis of neuroblastoma cells. Mol Cancer Ther 11:1454–1466. doi:10.1158/1535-7163.MCT-12-0001
Liu L, Wu J, Ying Z, Chen B, Han A, Liang Y, Song L, Yuan J, Li J, Li M (2010) Astrocyte elevated gene-1 upregulates matrix metalloproteinase-9 and induces human glioma invasion. Cancer Res 70:3750–3759. doi:10.1158/0008-5472.CAN-09-3838
Crea F, Fornaro L, Bocci G, Sun L, Farrar WL, Falcone A, Danesi R (2012) EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis. Cancer Metastasis Rev 31:753–761. doi:10.1007/s10555-012-9387-3
Lu C, Han HD, Mangala LS, Ali-Fehmi R, Newton CS, Ozbun L, Armaiz-Pena GN, Hu W, Stone RL, Munkarah A, Ravoori MK, Shahzad MM, Lee JW, Mora E, Langley RR, Carroll AR, Matsuo K, Spannuth WA, Schmandt R, Jennings NB, Goodman BW, Jaffe RB, Nick AM, Kim HS, Guven EO, Chen YH, Li LY, Hsu MC, Coleman RL, Calin GA, Denkbas EB, Lim JY, Lee JS, Kundra V, Birrer MJ, Hung MC, Lopez-Berestein G, Sood AK (2010) Regulation of tumor angiogenesis by EZH2. Cancer Cell 18:185–197. doi:10.1016/j.ccr.2010.06.016
Orzan F, Pellegatta S, Poliani PL, Pisati F, Caldera V, Menghi F, Kapetis D, Marras C, Schiffer D, Finocchiaro G (2011) Enhancer of Zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells. Neuropathol Appl Neurobiol 37:381–394. doi:10.1111/j.1365-2990.2010.01132.x
Wu Z, Wang Q, Wang L, Li G, Liu H, Fan F, Li Z, Li Y, Tu Y (2013) Combined aberrant expression of Bmi1 and EZH2 is predictive of poor prognosis in glioma patients. J Neurol Sci 335:191–196. doi:10.1016/j.jns.2013.09.030
Wu ZL, Zheng SS, Li ZM, Qiao YY, Aau MY, Yu Q (2010) Polycomb protein EZH2 regulates E2F1-dependent apoptosis through epigenetically modulating Bim expression. Cell Death Differ 17:801–810. doi:10.1038/cdd.2009.162
Wang D, Qiu C, Zhang H, Wang J, Cui Q, Yin Y (2010) Human microRNA oncogenes and tumor suppressors show significantly different biological patterns: from functions to targets. PloS One. doi:10.1371/journal.pone.0013067
Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, Clark KR, Mendell JR, Mendell JT (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137:1005–1017. doi:10.1016/j.cell.2009.04.021
Bader AG, Brown D, Winkler M (2010) The promise of microRNA replacement therapy. Cancer Res 70:7027–7030. doi:10.1158/0008-5472.CAN-10-2010
Bier A, Giladi N, Kronfeld N, Lee HK, Cazacu S, Finniss S, Xiang C, Poisson L, de Carvalho AC, Slavin S, Jacoby E, Yalon M, Toren A, Mikkelsen T, Brodie C (2013) MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting RTVP-1. Oncotarget 4:665–676
Karsy M, Arslan E, Moy F (2012) Current Progress on Understanding MicroRNAs in Glioblastoma Multiforme. Genes Cancer 3:3–15. doi:10.1177/1947601912448068
Chen L, Wang X, Wang H, Li Y, Yan W, Han L, Zhang K, Zhang J, Wang Y, Feng Y, Pu P, Jiang T, Kang C, Jiang C (2012) miR-137 is frequently down-regulated in glioblastoma and is a negative regulator of Cox-2. Eur J Cancer 48:3104–3111. doi:10.1016/j.ejca.2012.02.007
Sparmann A, van Lohuizen M (2006) Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 6:846–856. doi:10.1038/nrc1991
Simon JA, Lange CA (2008) Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res 647:21–29. doi:10.1016/j.mrfmmm.2008.07.010
Smits M, Nilsson J, Mir SE, van der Stoop PM, Hulleman E, Niers JM, de Witt Hamer PC, Marquez VE, Cloos J, Krichevsky AM, Noske DP, Tannous BA, Wurdinger T (2010) miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. Oncotarget 1:710–720
Suva ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC, Baumer K, Le Bitoux MA, Marino D, Cironi L, Marquez VE, Clement V, Stamenkovic I (2009) EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer research 69:9211–9218. doi:10.1158/0008-5472.CAN-09-1622
Bryant RJ, Cross NA, Eaton CL, Hamdy FC, Cunliffe VT (2007) EZH2 promotes proliferation and invasiveness of prostate cancer cells. Prostate 67:547–556. doi:10.1002/pros.20550
Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, Salvesen HB, Otte AP, Akslen LA (2006) EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 24:268–273. doi:10.1200/JCO.2005.01.5180
Li G, Warden C, Zou Z, Neman J, Krueger JS, Jain A, Jandial R, Chen M (2013) Altered expression of polycomb group genes in glioblastoma multiforme. PloS One 8:e80970. doi:10.1371/journal.pone.0080970
Szulwach KE, Li X, Smrt RD, Li Y, Luo Y, Lin L, Santistevan NJ, Li W, Zhao X, Jin P (2010) Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol 189:127–141. doi:10.1083/jcb.200908151
Bossel Ben-Moshe N, Avraham R, Kedmi M, Zeisel A, Yitzhaky A, Yarden Y, Domany E (2012) Context-specific microRNA analysis: identification of functional microRNAs and their mRNA targets. Nucleic Acids Res 40:10614–10627. doi:10.1093/nar/gks841
Li KK, Yang L, Pang JC, Chan AK, Zhou L, Mao Y, Wang Y, Lau KM, Poon WS, Shi Z, Ng HK (2013) MIR-137 suppresses growth and invasion, is downregulated in oligodendroglial tumors and targets CSE1L. Brain Pathol 23:426–439. doi:10.1111/bpa.12015
Author information
Authors and Affiliations
Corresponding authors
Additional information
Jie Sun and Guodong Zheng have contributed equally to this study.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Sun, J., Zheng, G., Gu, Z. et al. MiR-137 inhibits proliferation and angiogenesis of human glioblastoma cells by targeting EZH2. J Neurooncol 122, 481–489 (2015). https://doi.org/10.1007/s11060-015-1753-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-015-1753-x