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

  • Laboratory Investigation
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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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References

  1. 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

    Article  CAS  PubMed  Google Scholar 

  2. 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 11:6149–6157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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 16:1734–1745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Shah N, Sukumar S (2010) The Hox genes and their roles in oncogenesis. Nat Rev Cancer 10:361–371. doi:10.1038/nrc2826

    Article  CAS  PubMed  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. Han HB, Gu J, Ji DB, Li ZW, Zhang Y, Zhao W, Wang LM, Zhang ZQ (2014) PBX3 promotes migration and invasion of colorectal cancer cells via activation of MAPK/ERK signaling pathway. World J Gastroenterol 20:18260–18270. doi:10.3748/wjg.v20.i48.18260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li Y, Sun Z, Zhu Z, Zhang J, Sun X, Xu H (2014) PBX3 is overexpressed in gastric cancer and regulates cell proliferation. Tumour Biol 35:4363–4368. doi:10.1007/s13277-013-1573-6

    Article  CAS  PubMed  Google Scholar 

  8. 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

    Article  CAS  PubMed  Google Scholar 

  9. Li B, Zhang S, Shen H, Li C (2017) MicroRNA-144-3p suppresses gastric cancer progression by inhibiting epithelial-to-mesenchymal transition through targeting PBX3. Biochem Biophys Res Commun 484:241–247. doi:10.1016/j.bbrc.2017.01.084

    Article  CAS  PubMed  Google Scholar 

  10. Xu X, Bao Z, Liu Y, Ji J, Liu N (2017) MicroRNA-98 attenuates cell migration and invasion in glioma by directly targeting pre-b cell leukemia homeobox 3. Cell Mol Neurobiol. doi:10.1007/s10571-017-0466-4

    PubMed Central  Google Scholar 

  11. Laurent A, Bihan R, Omilli F, Deschamps S, Pellerin I (2008) PBX proteins: much more than Hox cofactors. Int J Dev Biol 52:9–20. doi:10.1387/ijdb.072304al

    Article  CAS  PubMed  Google Scholar 

  12. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512

    Article  CAS  PubMed  Google Scholar 

  13. Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9:153–166. doi:10.1038/nrc2602

    Article  CAS  PubMed  Google Scholar 

  14. Han Y, Wu Z, Wu T, Huang Y, Cheng Z, Li X, Sun T, Xie X, Zhou Y, Du Z (2016) Tumor-suppressive function of long noncoding RNA MALAT1 in glioma cells by downregulation of MMP2 and inactivation of ERK/MAPK signaling. Cell Death Dis 7:e2123. doi:10.1038/cddis.2015.407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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

    Article  PubMed  PubMed Central  Google Scholar 

  16. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Duan R, Han L, Wang Q, Wei J, Chen L, Zhang J, Kang C, Wang L (2015) HOXA13 is a potential GBM diagnostic marker and promotes glioma invasion by activating the Wnt and TGF-beta pathways. Oncotarget 6:27778–27793. doi:10.18632/oncotarget.4813

    Article  PubMed  PubMed Central  Google Scholar 

  18. 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

    Article  PubMed  Google Scholar 

  19. 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

    Article  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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

    Article  CAS  PubMed  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. 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

    Google Scholar 

  26. Lu Y, Wu D, Wang J, Li Y, Chai X, Kang Q (2016) miR-320a regulates cell proliferation and apoptosis in multiple myeloma by targeting pre-B-cell leukemia transcription factor 3. Biochem Biophys Res Commun 473:1315–1320. doi:10.1016/j.bbrc.2016.04.069

    Article  CAS  PubMed  Google Scholar 

  27. 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

    Article  CAS  PubMed  Google Scholar 

  28. Ramberg H, Alshbib A, Berge V, Svindland A, Tasken KA (2011) Regulation of PBX3 expression by androgen and Let-7d in prostate cancer. Mol Cancer 10:50. doi:10.1186/1476-4598-10-50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research was funded by the National Natural Science Foundation of China (81300998 and 81471269), National Natural Science Foundation of Jiangsu Province (BK20131022 and BK20160047), Jiangsu Province’s Key Discipline of Medicine (XK201117), Jiangsu Province and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Specially-Appointed Professor Foundation of Jiangsu Province (ky216r201307).

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    1. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 222000, Jiangsu, China

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

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    1. Xiupeng Xu
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    2. Ning Cai
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    3. Zhongyuan Bao
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    Correspondence to Ning Liu.

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    All the experiments in this article comply with the current laws of China.

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    Xiupeng Xu, Ning Cai, and Zhongyuan Bao have contributed equally to this work.

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    Xu, X., Cai, N., Bao, Z. et al. Silencing Pre-B-cell leukemia homeobox 3 decreases the proliferation of human glioma cells in vitro and in vivo. J Neurooncol 135, 453–463 (2017). https://doi.org/10.1007/s11060-017-2603-9

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