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Published in: Journal of Neuro-Oncology 3/2017

01-12-2017 | Laboratory Investigation

Silencing Pre-B-cell leukemia homeobox 3 decreases the proliferation of human glioma cells in vitro and in vivo

Authors: Xiupeng Xu, Ning Cai, Zhongyuan Bao, Yongping You, Jing Ji, Ning Liu

Published in: Journal of Neuro-Oncology | Issue 3/2017

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Abstract

Among primary brain tumors, gliomas are the most common and most aggressive, with a poor prognosis and limited treatment options. Thus, it is essential to determine the mechanisms involved in glioma development to develop effective therapies for glioma patients. Pre-B-cell leukemia homeobox 3 (PBX3), a critical member of the PBX family, is frequently overexpressed in multiple human malignancies. However, the expression patterns and biological functions, as well as the involved molecular functions of PBX3 in human gliomas remain largely unknown. In this study, we demonstrate that PBX3 expression is increased in both human glioma tissues and cell lines compared with their normal counterparts. These results suggested that PBX3 might be involved in glioma progression. Thus, the role of PBX3 in glioma cell proliferation was investigated using genetic knockdown and overexpression methods. The results showed that PBX3 knockdown inhibited glioma cell proliferation and induced apoptosis, while PBX3 overexpression significantly promoted glioma cell proliferation. Mechanistically, we found that PBX3 promoted cell proliferation by modulating cell cycle progression. A xenograft LN229 model was used to confirm that PBX3 depletion decreased tumor growth in vivo. In summary, our findings reveal that PBX3 may be a potential therapeutic target in gliomas.
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Literature
1.
go back to reference Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330 CrossRefPubMed Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.​1056/​NEJMoa043330 CrossRefPubMed
2.
go back to reference Monica K, Galili N, Nourse J, Saltman D, Cleary ML (1991) PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1. Mol Cell Biol 11:6149–6157CrossRefPubMedPubMedCentral Monica K, Galili N, Nourse J, Saltman D, Cleary ML (1991) PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1. Mol Cell Biol 11:6149–6157CrossRefPubMedPubMedCentral
3.
go back to reference Chang CP, Brocchieri L, Shen WF, Largman C, Cleary ML (1996) Pbx modulation of Hox homeodomain amino-terminal arms establishes different DNA-binding specificities across the Hox locus. Mol Cell Biol 16:1734–1745CrossRefPubMedPubMedCentral Chang CP, Brocchieri L, Shen WF, Largman C, Cleary ML (1996) Pbx modulation of Hox homeodomain amino-terminal arms establishes different DNA-binding specificities across the Hox locus. Mol Cell Biol 16:1734–1745CrossRefPubMedPubMedCentral
5.
go back to reference Han H, Du Y, Zhao W, Li S, Chen D, Zhang J, Liu J, Suo Z, Bian X, Xing B, Zhang Z (2015) PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells. Nat Commun 6:8271. doi:10.1038/ncomms9271 CrossRefPubMed Han H, Du Y, Zhao W, Li S, Chen D, Zhang J, Liu J, Suo Z, Bian X, Xing B, Zhang Z (2015) PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells. Nat Commun 6:8271. doi:10.​1038/​ncomms9271 CrossRefPubMed
8.
go back to reference Ramberg H, Grytli HH, Nygard S, Wang W, Ogren O, Zhao S, Lovf M, Katz B, Skotheim RI, Bjartell A, Eri LM, Berge V, Svindland A, Tasken KA (2016) PBX3 is a putative biomarker of aggressive prostate cancer. Int J Cancer 139:1810–1820. doi:10.1002/ijc.30220 CrossRefPubMed Ramberg H, Grytli HH, Nygard S, Wang W, Ogren O, Zhao S, Lovf M, Katz B, Skotheim RI, Bjartell A, Eri LM, Berge V, Svindland A, Tasken KA (2016) PBX3 is a putative biomarker of aggressive prostate cancer. Int J Cancer 139:1810–1820. doi:10.​1002/​ijc.​30220 CrossRefPubMed
12.
go back to reference Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512CrossRefPubMed Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512CrossRefPubMed
15.
go back to reference Jones TA, Jeyapalan JN, Forshew T, Tatevossian RG, Lawson AR, Patel SN, Doctor GT, Mumin MA, Picker SR, Phipps KP, Michalski A, Jacques TS, Sheer D (2015) Molecular analysis of pediatric brain tumors identifies microRNAs in pilocytic astrocytomas that target the MAPK and NF-kappaB pathways. Acta Neuropathol Commun 3:86. doi:10.1186/s40478-015-0266-3 CrossRefPubMedPubMedCentral Jones TA, Jeyapalan JN, Forshew T, Tatevossian RG, Lawson AR, Patel SN, Doctor GT, Mumin MA, Picker SR, Phipps KP, Michalski A, Jacques TS, Sheer D (2015) Molecular analysis of pediatric brain tumors identifies microRNAs in pilocytic astrocytomas that target the MAPK and NF-kappaB pathways. Acta Neuropathol Commun 3:86. doi:10.​1186/​s40478-015-0266-3 CrossRefPubMedPubMedCentral
16.
go back to reference Li Z, Zhang Z, Li Y, Arnovitz S, Chen P, Huang H, Jiang X, Hong GM, Kunjamma RB, Ren H, He C, Wang CZ, Elkahloun AG, Valk PJ, Dohner K, Neilly MB, Bullinger L, Delwel R, Lowenberg B, Liu PP, Morgan R, Rowley JD, Yuan CS, Chen J (2013) PBX3 is an important cofactor of HOXA9 in leukemogenesis. Blood 121:1422–1431. doi:10.1182/blood-2012-07-442004 CrossRefPubMedPubMedCentral Li Z, Zhang Z, Li Y, Arnovitz S, Chen P, Huang H, Jiang X, Hong GM, Kunjamma RB, Ren H, He C, Wang CZ, Elkahloun AG, Valk PJ, Dohner K, Neilly MB, Bullinger L, Delwel R, Lowenberg B, Liu PP, Morgan R, Rowley JD, Yuan CS, Chen J (2013) PBX3 is an important cofactor of HOXA9 in leukemogenesis. Blood 121:1422–1431. doi:10.​1182/​blood-2012-07-442004 CrossRefPubMedPubMedCentral
18.
go back to reference Di Vinci A, Casciano I, Marasco E, Banelli B, Ravetti GL, Borzi L, Brigati C, Forlani A, Dorcaratto A, Allemanni G, Zona G, Spaziante R, Gohlke H, Gardin G, Merlo DF, Mantovani V, Romani M (2012) Quantitative methylation analysis of HOXA3, 7, 9, and 10 genes in glioma: association with tumor WHO grade and clinical outcome. J Cancer Res Clin Oncol 138:35–47. doi:10.1007/s00432-011-1070-5 CrossRefPubMed Di Vinci A, Casciano I, Marasco E, Banelli B, Ravetti GL, Borzi L, Brigati C, Forlani A, Dorcaratto A, Allemanni G, Zona G, Spaziante R, Gohlke H, Gardin G, Merlo DF, Mantovani V, Romani M (2012) Quantitative methylation analysis of HOXA3, 7, 9, and 10 genes in glioma: association with tumor WHO grade and clinical outcome. J Cancer Res Clin Oncol 138:35–47. doi:10.​1007/​s00432-011-1070-5 CrossRefPubMed
19.
go back to reference Xu Z, Zeng X, Xu J, Xu D, Li J, Jin H, Jiang G, Han X, Huang C (2016) Isorhapontigenin suppresses growth of patient-derived glioblastoma spheres through regulating miR-145/SOX2/cyclin D1 axis. Neuro-oncol 18:830–839. doi:10.1093/neuonc/nov298 CrossRefPubMed Xu Z, Zeng X, Xu J, Xu D, Li J, Jin H, Jiang G, Han X, Huang C (2016) Isorhapontigenin suppresses growth of patient-derived glioblastoma spheres through regulating miR-145/SOX2/cyclin D1 axis. Neuro-oncol 18:830–839. doi:10.​1093/​neuonc/​nov298 CrossRefPubMed
20.
go back to reference Suva ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, Riggi N, Chi AS, Cahill DP, Nahed BV, Curry WT, Martuza RL, Rivera MN, Rossetti N, Kasif S, Beik S, Kadri S, Tirosh I, Wortman I, Shalek AK, Rozenblatt-Rosen O, Regev A, Louis DN, Bernstein BE (2014) Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 157:580–594. doi:10.1016/j.cell.2014.02.030 CrossRefPubMedPubMedCentral Suva ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, Riggi N, Chi AS, Cahill DP, Nahed BV, Curry WT, Martuza RL, Rivera MN, Rossetti N, Kasif S, Beik S, Kadri S, Tirosh I, Wortman I, Shalek AK, Rozenblatt-Rosen O, Regev A, Louis DN, Bernstein BE (2014) Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 157:580–594. doi:10.​1016/​j.​cell.​2014.​02.​030 CrossRefPubMedPubMedCentral
21.
go back to reference Chen X, Ma WY, Xu SC, Liang Y, Fu YB, Pang B, Xin T, Fan HT, Zhang R, Luo JG, Kang WQ, Wang M, Pang Q (2014) The overexpression of epithelial cell adhesion molecule (EpCAM) in glioma. J Neurooncol 119:39–47. doi:10.1007/s11060-014-1459-5 CrossRefPubMed Chen X, Ma WY, Xu SC, Liang Y, Fu YB, Pang B, Xin T, Fan HT, Zhang R, Luo JG, Kang WQ, Wang M, Pang Q (2014) The overexpression of epithelial cell adhesion molecule (EpCAM) in glioma. J Neurooncol 119:39–47. doi:10.​1007/​s11060-014-1459-5 CrossRefPubMed
22.
go back to reference Lopez-Bertoni H, Lal B, Li A, Caplan M, Guerrero-Cazares H, Eberhart CG, Quinones-Hinojosa A, Glas M, Scheffler B, Laterra J, Li Y (2015) DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2. Oncogene 34:3994–4004. doi:10.1038/onc.2014.334 CrossRefPubMed Lopez-Bertoni H, Lal B, Li A, Caplan M, Guerrero-Cazares H, Eberhart CG, Quinones-Hinojosa A, Glas M, Scheffler B, Laterra J, Li Y (2015) DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2. Oncogene 34:3994–4004. doi:10.​1038/​onc.​2014.​334 CrossRefPubMed
23.
go back to reference Dell’albani P, Rodolico M, Pellitteri R, Tricarichi E, Torrisi SA, D’Antoni S, Zappia M, Albanese V, Caltabiano R, Platania N, Aronica E, Catania MV (2014) Differential patterns of NOTCH1-4 receptor expression are markers of glioma cell differentiation. Neuro-oncol 16:204–216. doi:10.1093/neuonc/not168 CrossRefPubMed Dell’albani P, Rodolico M, Pellitteri R, Tricarichi E, Torrisi SA, D’Antoni S, Zappia M, Albanese V, Caltabiano R, Platania N, Aronica E, Catania MV (2014) Differential patterns of NOTCH1-4 receptor expression are markers of glioma cell differentiation. Neuro-oncol 16:204–216. doi:10.​1093/​neuonc/​not168 CrossRefPubMed
24.
go back to reference Ordway JM, Bedell JA, Citek RW, Nunberg A, Garrido A, Kendall R, Stevens JR, Cao D, Doerge RW, Korshunova Y, Holemon H, McPherson JD, Lakey N, Leon J, Martienssen RA, Jeddeloh JA (2006) Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets. Carcinogenesis 27:2409–2423. doi:10.1093/carcin/bgl161 CrossRefPubMed Ordway JM, Bedell JA, Citek RW, Nunberg A, Garrido A, Kendall R, Stevens JR, Cao D, Doerge RW, Korshunova Y, Holemon H, McPherson JD, Lakey N, Leon J, Martienssen RA, Jeddeloh JA (2006) Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets. Carcinogenesis 27:2409–2423. doi:10.​1093/​carcin/​bgl161 CrossRefPubMed
25.
go back to reference Han SY, Han HB, Tian XY, Sun H, Xue D, Zhao C, Jiang ST, He XR, Zheng WX, Wang J, Pang LN, Li XH, Li PP (2016) MicroRNA-33a-3p suppresses cell migration and invasion by directly targeting PBX3 in human hepatocellular carcinoma. Oncotarget. doi:10.18632/oncotarget.9886 Han SY, Han HB, Tian XY, Sun H, Xue D, Zhao C, Jiang ST, He XR, Zheng WX, Wang J, Pang LN, Li XH, Li PP (2016) MicroRNA-33a-3p suppresses cell migration and invasion by directly targeting PBX3 in human hepatocellular carcinoma. Oncotarget. doi:10.​18632/​oncotarget.​9886
27.
go back to reference Han HB, Gu J, Zuo HJ, Chen ZG, Zhao W, Li M, Ji DB, Lu YY, Zhang ZQ (2012) Let-7c functions as a metastasis suppressor by targeting MMP11 and PBX3 in colorectal cancer. J Pathol 226:544–555. doi:10.1002/path.3014 CrossRefPubMed Han HB, Gu J, Zuo HJ, Chen ZG, Zhao W, Li M, Ji DB, Lu YY, Zhang ZQ (2012) Let-7c functions as a metastasis suppressor by targeting MMP11 and PBX3 in colorectal cancer. J Pathol 226:544–555. doi:10.​1002/​path.​3014 CrossRefPubMed
Metadata
Title
Silencing Pre-B-cell leukemia homeobox 3 decreases the proliferation of human glioma cells in vitro and in vivo
Authors
Xiupeng Xu
Ning Cai
Zhongyuan Bao
Yongping You
Jing Ji
Ning Liu
Publication date
01-12-2017
Publisher
Springer US
Published in
Journal of Neuro-Oncology / Issue 3/2017
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-017-2603-9

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