Skip to main content
Top
Published in: Journal of Neuro-Oncology 2/2013

01-11-2013 | Laboratory Investigation

MiR-29c inhibits glioma cell proliferation, migration, invasion and angiogenesis

Published in: Journal of Neuro-Oncology | Issue 2/2013

Login to get access

Abstract

Previous studies reported that miR-29c is significantly downregulated in several tumors. However, little is known about the effect and molecular mechanisms of action of miR-29c in human glioma. Using quantitative RT-PCR, we demonstrated that miR-29c was significantly downregulated in glioma cell lines and human primary glioma tissues, compared to normal human astrocytes and matched non-tumor associated tissues (P < 0.05, χ2 test). Overexpression of miR-29c dramatically reduced the proliferation and caused cessation of cell cycle. The reduced cell proliferation is due to G1 phase arrest as cyclin D1 and cyclin E are diminished whereas p27 and p21 are upregulated. We further demonstrated that miR-29c overexpression suppressed the glioma cell migration and invasion abilities by targeting MMP-2. In addition, we also found that overexpression of miR-29c sharply inhibited angiogenesis, which correlated with down-regulation of VEGF. The data indicate that miR-29c may be a tumor suppressor involved in the progression of glioma.
Appendix
Available only for authorised users
Literature
2.
go back to reference 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 Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups, National Cancer Institute of Canada Clinical Trials Group (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(5):459–466. doi:10.1016/S1470-2045(09)70025-7 PubMedCrossRef 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 Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups, National Cancer Institute of Canada Clinical Trials Group (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(5):459–466. doi:10.​1016/​S1470-2045(09)70025-7 PubMedCrossRef
4.
5.
go back to reference Zaravinos A, Radojicic J, Lambrou GI, Volanis D, Delakas D, Stathopoulos EN, Spandidos DA (2012) Expression of miRNAs involved in angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial–mesenchymal transition and activation of metastasis in bladder cancer. J Urol 188(2):615–623. doi:10.1016/j.juro.2012.03.122 PubMedCrossRef Zaravinos A, Radojicic J, Lambrou GI, Volanis D, Delakas D, Stathopoulos EN, Spandidos DA (2012) Expression of miRNAs involved in angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial–mesenchymal transition and activation of metastasis in bladder cancer. J Urol 188(2):615–623. doi:10.​1016/​j.​juro.​2012.​03.​122 PubMedCrossRef
6.
go back to reference Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A (2004) High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosomes Cancer 39(2):167–169. doi:10.1002/gcc.10316 PubMedCrossRef Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A (2004) High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosomes Cancer 39(2):167–169. doi:10.​1002/​gcc.​10316 PubMedCrossRef
7.
go back to reference Michael MZ, O’ Connor SM, van Holst Pellekaan NG, Young GP, James RJ (2003) Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 1(12):882–891PubMed Michael MZ, O’ Connor SM, van Holst Pellekaan NG, Young GP, James RJ (2003) Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 1(12):882–891PubMed
8.
go back to reference Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64(11):3753–3756. doi:10.1158/0008-5472.CAN-04-0637 PubMedCrossRef Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64(11):3753–3756. doi:10.​1158/​0008-5472.​CAN-04-0637 PubMedCrossRef
9.
go back to reference Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Menard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65(16):7065–7070. doi:10.1158/0008-5472.CAN-05-1783 PubMedCrossRef Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Menard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65(16):7065–7070. doi:10.​1158/​0008-5472.​CAN-05-1783 PubMedCrossRef
10.
go back to reference Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, Shimotohno K (2006) Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 25(17):2537–2545. doi:10.1038/sj.onc.1209283 PubMedCrossRef Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, Shimotohno K (2006) Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 25(17):2537–2545. doi:10.​1038/​sj.​onc.​1209283 PubMedCrossRef
11.
14.
go back to reference Wang W, Dai LX, Zhang S, Yang Y, Yan N, Fan P, Dai L, Tian HW, Cheng L, Zhang XM, Li C, Zhang JF, Xu F, Shi G, Chen XL, Du T, Li YM, Wei YQ, Deng HX (2013) Regulation of epidermal growth factor receptor signaling by plasmid-based microRNA-7 inhibits human malignant gliomas growth and metastasis in vivo. Neoplasma 60(3):274–283. doi:10.4149/neo_2013_036 PubMedCrossRef Wang W, Dai LX, Zhang S, Yang Y, Yan N, Fan P, Dai L, Tian HW, Cheng L, Zhang XM, Li C, Zhang JF, Xu F, Shi G, Chen XL, Du T, Li YM, Wei YQ, Deng HX (2013) Regulation of epidermal growth factor receptor signaling by plasmid-based microRNA-7 inhibits human malignant gliomas growth and metastasis in vivo. Neoplasma 60(3):274–283. doi:10.​4149/​neo_​2013_​036 PubMedCrossRef
15.
go back to reference Papagiannakopoulos T, Friedmann-Morvinski D, Neveu P, Dugas JC, Gill RM, Huillard E, Liu C, Zong H, Rowitch DH, Barres BA, Verma IM, Kosik KS (2012) Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene 31(15):1884–1895. doi:10.1038/onc.2011.380 PubMedCrossRef Papagiannakopoulos T, Friedmann-Morvinski D, Neveu P, Dugas JC, Gill RM, Huillard E, Liu C, Zong H, Rowitch DH, Barres BA, Verma IM, Kosik KS (2012) Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene 31(15):1884–1895. doi:10.​1038/​onc.​2011.​380 PubMedCrossRef
16.
go back to reference Sengupta S, den Boon JA, Chen IH, Newton MA, Stanhope SA, Cheng YJ, Chen CJ, Hildesheim A, Sugden B, Ahlquist P (2008) MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc Natl Acad Sci USA 105(15):5874–5878. doi:10.1073/pnas.0801130105 PubMedCentralPubMedCrossRef Sengupta S, den Boon JA, Chen IH, Newton MA, Stanhope SA, Cheng YJ, Chen CJ, Hildesheim A, Sugden B, Ahlquist P (2008) MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc Natl Acad Sci USA 105(15):5874–5878. doi:10.​1073/​pnas.​0801130105 PubMedCentralPubMedCrossRef
18.
go back to reference Friedman JM, Liang G, Liu CC, Wolff EM, Tsai YC, Ye W, Zhou X, Jones PA (2009) The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res 69(6):2623–2629. doi:10.1158/0008-5472.CAN-08-3114 PubMedCrossRef Friedman JM, Liang G, Liu CC, Wolff EM, Tsai YC, Ye W, Zhou X, Jones PA (2009) The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res 69(6):2623–2629. doi:10.​1158/​0008-5472.​CAN-08-3114 PubMedCrossRef
19.
go back to reference Guo Y, Chen Z, Zhang L, Zhou F, Shi S, Feng X, Li B, Meng X, Ma X, Luo M, Shao K, Li N, Qiu B, Mitchelson K, Cheng J, He J (2008) Distinctive microRNA profiles relating to patient survival in esophageal squamous cell carcinoma. Cancer Res 68(1):26–33. doi:10.1158/0008-5472.CAN-06-4418 PubMedCrossRef Guo Y, Chen Z, Zhang L, Zhou F, Shi S, Feng X, Li B, Meng X, Ma X, Luo M, Shao K, Li N, Qiu B, Mitchelson K, Cheng J, He J (2008) Distinctive microRNA profiles relating to patient survival in esophageal squamous cell carcinoma. Cancer Res 68(1):26–33. doi:10.​1158/​0008-5472.​CAN-06-4418 PubMedCrossRef
20.
go back to reference Stamatopoulos B, Meuleman N, Haibe-Kains B, Saussoy P, Van Den Neste E, Michaux L, Heimann P, Martiat P, Bron D, Lagneaux L (2009) microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification. Blood 113(21):5237–5245. doi:10.1182/blood-2008-11-189407 PubMedCrossRef Stamatopoulos B, Meuleman N, Haibe-Kains B, Saussoy P, Van Den Neste E, Michaux L, Heimann P, Martiat P, Bron D, Lagneaux L (2009) microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification. Blood 113(21):5237–5245. doi:10.​1182/​blood-2008-11-189407 PubMedCrossRef
22.
go back to reference Li Y, Wang F, Xu J, Ye F, Shen Y, Zhou J, Lu W, Wan X, Ma D, Xie X (2011) Progressive miRNA expression profiles in cervical carcinogenesis and identification of HPV-related target genes for miR-29. J Pathol 224(4):484–495. doi:10.1002/path.2873 PubMedCrossRef Li Y, Wang F, Xu J, Ye F, Shen Y, Zhou J, Lu W, Wan X, Ma D, Xie X (2011) Progressive miRNA expression profiles in cervical carcinogenesis and identification of HPV-related target genes for miR-29. J Pathol 224(4):484–495. doi:10.​1002/​path.​2873 PubMedCrossRef
23.
go back to reference Xiong Y, Fang JH, Yun JP, Yang J, Zhang Y, Jia WH, Zhuang SM (2010) Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology 51(3):836–845. doi:10.1002/hep.23380 PubMed Xiong Y, Fang JH, Yun JP, Yang J, Zhang Y, Jia WH, Zhuang SM (2010) Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology 51(3):836–845. doi:10.​1002/​hep.​23380 PubMed
24.
go back to reference Nguyen T, Kuo C, Nicholl MB, Sim MS, Turner RR, Morton DL, Hoon DS (2011) Downregulation of microRNA-29c is associated with hypermethylation of tumor-related genes and disease outcome in cutaneous melanoma. Epigenetics 6(3):388–394PubMedCentralPubMedCrossRef Nguyen T, Kuo C, Nicholl MB, Sim MS, Turner RR, Morton DL, Hoon DS (2011) Downregulation of microRNA-29c is associated with hypermethylation of tumor-related genes and disease outcome in cutaneous melanoma. Epigenetics 6(3):388–394PubMedCentralPubMedCrossRef
25.
go back to reference Tanaka H, Sasayama T, Tanaka K, Nakamizo S, Nishihara M, Mizukawa K, Kohta M, Koyama J, Miyake S, Taniguchi M, Hosoda K, Kohmura E (2013) MicroRNA-183 upregulates HIF-1alpha by targeting isocitrate dehydrogenase 2 (IDH2) in glioma cells. J Neurooncol 111(3):273–283. doi:10.1007/s11060-012-1027-9 PubMedCrossRef Tanaka H, Sasayama T, Tanaka K, Nakamizo S, Nishihara M, Mizukawa K, Kohta M, Koyama J, Miyake S, Taniguchi M, Hosoda K, Kohmura E (2013) MicroRNA-183 upregulates HIF-1alpha by targeting isocitrate dehydrogenase 2 (IDH2) in glioma cells. J Neurooncol 111(3):273–283. doi:10.​1007/​s11060-012-1027-9 PubMedCrossRef
26.
go back to reference Bai J, Mei PJ, Liu H, Li C, Li W, Wu YP, Yu ZQ, Zheng JN (2012) BRG1 expression is increased in human glioma and controls glioma cell proliferation, migration and invasion in vitro. J Cancer Res Clin Oncol 138(6):991–998. doi:10.1007/s00432-012-1172-8 PubMedCrossRef Bai J, Mei PJ, Liu H, Li C, Li W, Wu YP, Yu ZQ, Zheng JN (2012) BRG1 expression is increased in human glioma and controls glioma cell proliferation, migration and invasion in vitro. J Cancer Res Clin Oncol 138(6):991–998. doi:10.​1007/​s00432-012-1172-8 PubMedCrossRef
27.
go back to reference Mei PJ, Bai J, Liu H, Li C, Wu YP, Yu ZQ, Zheng JN (2011) RUNX3 expression is lost in glioma and its restoration causes drastic suppression of tumor invasion and migration. J Cancer Res Clin Oncol 137(12):1823–1830. doi:10.1007/s00432-011-1063-4 PubMedCrossRef Mei PJ, Bai J, Liu H, Li C, Wu YP, Yu ZQ, Zheng JN (2011) RUNX3 expression is lost in glioma and its restoration causes drastic suppression of tumor invasion and migration. J Cancer Res Clin Oncol 137(12):1823–1830. doi:10.​1007/​s00432-011-1063-4 PubMedCrossRef
30.
go back to reference 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 PubMedCentralPubMedCrossRef 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 PubMedCentralPubMedCrossRef
32.
go back to reference Zhang Y, Chao T, Li R, Liu W, Chen Y, Yan X, Gong Y, Yin B, Qiang B, Zhao J, Yuan J, Peng X (2009) MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a. J Mol Med (Berl) 87(1):43–51. doi:10.1007/s00109-008-0403-6 CrossRef Zhang Y, Chao T, Li R, Liu W, Chen Y, Yan X, Gong Y, Yin B, Qiang B, Zhao J, Yuan J, Peng X (2009) MicroRNA-128 inhibits glioma cells proliferation by targeting transcription factor E2F3a. J Mol Med (Berl) 87(1):43–51. doi:10.​1007/​s00109-008-0403-6 CrossRef
37.
go back to reference Lee MH, Yang HY (2003) Regulators of G1 cyclin-dependent kinases and cancers. Cancer Metastasis Rev 22(4):435–449PubMedCrossRef Lee MH, Yang HY (2003) Regulators of G1 cyclin-dependent kinases and cancers. Cancer Metastasis Rev 22(4):435–449PubMedCrossRef
38.
go back to reference Ding DP, Chen ZL, Zhao XH, Wang JW, Sun J, Wang Z, Tan FW, Tan XG, Li BZ, Zhou F, Shao K, Li N, Qiu B, He J (2011) miR-29c induces cell cycle arrest in esophageal squamous cell carcinoma by modulating cyclin E expression. Carcinogenesis 32(7):1025–1032. doi:10.1093/carcin/bgr078 PubMedCrossRef Ding DP, Chen ZL, Zhao XH, Wang JW, Sun J, Wang Z, Tan FW, Tan XG, Li BZ, Zhou F, Shao K, Li N, Qiu B, He J (2011) miR-29c induces cell cycle arrest in esophageal squamous cell carcinoma by modulating cyclin E expression. Carcinogenesis 32(7):1025–1032. doi:10.​1093/​carcin/​bgr078 PubMedCrossRef
40.
go back to reference Groblewska M, Siewko M, Mroczko B, Szmitkowski M (2012) The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer. Folia Histochem Cytobiol 50(1):12–19. doi:10.2478/18691 PubMedCrossRef Groblewska M, Siewko M, Mroczko B, Szmitkowski M (2012) The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer. Folia Histochem Cytobiol 50(1):12–19. doi:10.​2478/​18691 PubMedCrossRef
41.
go back to reference Tapia A, Salamonsen LA, Manuelpillai U, Dimitriadis E (2008) Leukemia inhibitory factor promotes human first trimester extravillous trophoblast adhesion to extracellular matrix and secretion of tissue inhibitor of metalloproteinases-1 and -2. Hum Reprod 23(8):1724–1732. doi:10.1093/humrep/den121 PubMedCentralPubMedCrossRef Tapia A, Salamonsen LA, Manuelpillai U, Dimitriadis E (2008) Leukemia inhibitory factor promotes human first trimester extravillous trophoblast adhesion to extracellular matrix and secretion of tissue inhibitor of metalloproteinases-1 and -2. Hum Reprod 23(8):1724–1732. doi:10.​1093/​humrep/​den121 PubMedCentralPubMedCrossRef
42.
go back to reference Sun ZF, Wang L, Gu F, Fu L, Li WL, Ma YJ (2012) Expression of Notch1, MMP-2 and MMP-9 and their significance in glioma patients. Zhonghua Zhong Liu Za Zhi 34(1):26–30PubMed Sun ZF, Wang L, Gu F, Fu L, Li WL, Ma YJ (2012) Expression of Notch1, MMP-2 and MMP-9 and their significance in glioma patients. Zhonghua Zhong Liu Za Zhi 34(1):26–30PubMed
43.
go back to reference Dhup S, Dadhich RK, Porporato PE, Sonveaux P (2012) Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr Pharm Des 18(10):1319–1330PubMedCrossRef Dhup S, Dadhich RK, Porporato PE, Sonveaux P (2012) Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr Pharm Des 18(10):1319–1330PubMedCrossRef
Metadata
Title
MiR-29c inhibits glioma cell proliferation, migration, invasion and angiogenesis
Publication date
01-11-2013
Published in
Journal of Neuro-Oncology / Issue 2/2013
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-013-1223-2

Other articles of this Issue 2/2013

Journal of Neuro-Oncology 2/2013 Go to the issue