Skip to main content

Prognostic value of NUSAP1 in progression and expansion of glioblastoma multiforme

Journal of Neuro-Oncology volume 140, pages 199–208 (2018)Cite this article

Abstract

Nucleolar and spindle-associated protein (NUSAP1) is a microtubule and chromatin-binding protein that stabilizes microtubules to prevent depolymerization, maintains spindle integrity. NUSAP1 could cross-link spindles into aster-like structures, networks and fibers. It has also been found to play roles in progression of several cancers. However, the potential correlation between NUSAP1 and clinical outcome in patients with glioblastoma multiforme (GBM) remains largely unknown. In the current study, we demonstrated that NUSAP1 was significantly up-regulated in GBM tissues compared with adult non-tumor brain tissues both in a validated cohort and a TCGA cohort. In addition, Kaplan–Meier analysis indicated that patients with high NUSAP1 expression had significantly lower OS (P = 0.0027). Additionally, in the TCGA cohort, NUSAP1 expression was relatively lower in GBM patients within the neural and mesenchymal subtypes compared to other subtypes, and associated with the status of several genetic aberrations such as PTEN deletion and wild type IDH1. The present study provides new insights and evidence that NUSAP1 over-expression was significantly correlated with progression and prognosis of GBM. Furthermore, knockdown of NUSAP1 revealed its regulation on G2/M progression and cell proliferation (both in vitro and in vivo). These data demonstrate that NUSAP1 could serve as a novel prognostic biomarker and a potential therapeutic target for GBM.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

GBM:

Glioblastoma multiforme

NUSAP1:

Nucleolar-spindle associated protein

TCGA:

The Cancer Genome Atlas

CNS:

Central nervous system

SPF:

Specific pathogen-free

shRNA:

Short hairpin RNA

qRT-PCR:

Quantitative real-time polymerase chain reaction

References

  1. Ostrom QT, Gittleman H, Farah P et al (2013) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol Suppl 2:ii1–ii56

    Google Scholar 

  2. Westphal M, Lamszus K (2011) The neurobiology of gliomas: from cell biology to the development of therapeutic approaches. Nat Rev Neurosci 12:495–508

    Article  CAS  PubMed  Google Scholar 

  3. Gilbert MR, Dignam JJ, Armstrong TS et al (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ohgaki H, Kleihues P (2005) Epidemiology and etiology of gliomas. Acta Neuropathol 109:93–108

    Article  PubMed  Google Scholar 

  5. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  Google Scholar 

  6. Tanaka S, Louis DN, Curry WT et al (2013) Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat Rev Clin Oncol 10:14–26

    Article  CAS  PubMed  Google Scholar 

  7. Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ (2010) Exciting new advances in neurooncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60:166–193

    Article  PubMed  PubMed Central  Google Scholar 

  8. Babae N, Bourajjaj M, Liu Y et al (2014) Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma. Oncotarget 5:6687–6700

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chen L, Liu X, Zhang HY et al (2014) Upregulation of chemokine receptor CCR10 is essential for glioma proliferation, invasion and patient survival. Oncotarget 5:6576–6583

    PubMed  PubMed Central  Google Scholar 

  10. Kim JW, Kim JY, Kim JE et al (2014) HOXA10 is associated with temozolomide resistance through regulation of the homologous recombinant DNA repair pathway in glioblastoma cell lines. Genes Cancer 5:165–174

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Paul I, Bhattacharya S, Chatterjee A,et al (2013) Current understanding on EGFR and Wnt/beta-catenin signaling in glioma and their possible crosstalk. Genes Cancer 4:427–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kitanaka C, Sato A, Okada M (2013) JNK signaling in the control of the tumor-initiating capacity associated with cancer stem cells. Genes Cancer 4:388–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Raemaekers T, Ribbeck K, Beaudouin J et al (2003) NuSAP, a novel microtubule-associated proteininvolved in mitotic spindle organization. J Cell Biol 162:1017–1029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vanden B, Raemaekers A, Denayer T et al (2010) NuSAP is essential for chromatin-induced spindle formation during early embryogenesis. J Cell Sci 123:3244–3255

    Article  CAS  Google Scholar 

  15. Ribbeck K, Groen AC, Santarella R et al (2006) NuSAP, a mitotic RanGTP target that stabilizes and cross-links microtubules. Mol Biol Cell 17:2646–2660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen DT, Nasir A, Culhane A et al (2010) Proliferative genes dominate malignancy-risk gene signature in histologically-normal breast tissue. Breast Cancer Res Treat 119:335–346

    Article  PubMed  Google Scholar 

  17. Satow R, Shitashige M, Kanai Y et al (2010) Combined functional genome survey of therapeutic targets for hepatocellular carcinoma. Clin Cancer Res 16:2518–2528

    Article  CAS  PubMed  Google Scholar 

  18. Kokkinakis DM, Liu X, Neuner RD (2005) Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma. Mol Cancer Ther 4:1338–1348

    Article  CAS  PubMed  Google Scholar 

  19. Chen Y, Wang Z, Dai X, Fei X, Shen Y, Zhang M, Wang A, Li X, Wang Z, Huang Q, Dong J (2015) Glioma initiating cells contribute to malignant transformation of host glial cells during tumor tissue remodeling via PDGF signaling. Cancer Lett 365(2):174–181

    Article  CAS  PubMed  Google Scholar 

  20. Huang Q, Zhang QB, Dong J, Wu YY, Shen YT, Zhao YD, Zhu YD, Diao Y, Wang AD, Lan Q (2008) Glioma stem cells are more aggressive in recurrent tumors with malignant progression than in the primary tumor, and both can be maintained long-term in vitro. BMC Cancer 8:304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408

    Article  CAS  Google Scholar 

  22. The Cancer Genome Atlas (TCGA) Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  CAS  Google Scholar 

  23. Hedditch EL, Gao B, Russell AJ et al (2014) ABCA transporter gene expression and poor outcome in epithelial ovarian cancer. J Natl Cancer Inst 106:149

    Article  CAS  Google Scholar 

  24. Chen QR, Hu Y, Yan C et al (2014) Systematic genetic analysis identifies Cis-eQTL target genes associated with glioblastoma patient survival. PLoS ONE 9:e105393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mao P, Hever-Jardine MP, Rahme GJ et al (2013) Serine/threonine kinase 17A is a novel candidate for therapeutic targeting in glioblastoma. PLoS ONE 8:e81803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Brunckhorst MK, Wang H, Lu R et al (2010) Angiopoietin-4 promotes glioblastoma progression by enhancing tumor cell viability and angiogenesis. Cancer Res 70:7283–7293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Djaafri I, Khayati F, Menashi S et al (2014) A novel tumor suppressor function of Kindlin-3 in solid cancer. Oncotarget 5:8970–8985

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jiang L, Yang YD, Fu L et al (2014) CLDN3 inhibits cancer aggressiveness via Wnt-EMT signaling and is a potential prognostic biomarker for hepatocellular carcinoma. Oncotarget 5:7663–7676

    PubMed  PubMed Central  Google Scholar 

  29. Park EY, Chang E, Lee EJ et al (2014) Targeting of miR34a-NOTCH1 axis reduced breast cancer stemness and chemoresistance. Cancer Res 74:7573–7582

    Article  CAS  PubMed  Google Scholar 

  30. Sainz B Jr, Martin B, Tatari M et al (2014) ISG15 is a criticalm microenvironmental factor for pancreatic cancer stem cells. Cancer Res 74:7309–7320

    Article  CAS  PubMed  Google Scholar 

  31. Yu H, Ye W, Wu J, Meng X, Liu RY, Ying X et al (2014) Overexpression of sirt7 exhibits oncogenic property and serves as a prognostic factor in colorectal cancer. Clin Cancer Res 20(13):3434–3445

    Article  CAS  PubMed  Google Scholar 

  32. Erhaak RG, Hoadley KA, Purdom E et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in DGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110

    Article  CAS  Google Scholar 

  33. Colak D, Nofal A, Albakheet A et al (2013) Age-specific gene expression signatures for breast tumors and cross-species conserved potential cancer progression markers in young women. PLoS ONE 8:e63204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gordon CA, Gulzar ZG, Brooks JD (2015) NUSAP1 expression is upregulated by loss of RB1 in prostate cancer cells. Prostate 75:517–526

    Article  CAS  PubMed  Google Scholar 

  35. de la Iglesia N, Konopka G, Puram SV et al (2008) Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev 22:449–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by National Natural Science Foundation of China (81472739; 81602183; 81702457), Natural Science Foundation of Jiangsu province, China (BK20151214).

Author information

Author notes

  1. Zhiyuan Qian, Yuping Li and Jiawei Ma have contributed equally to this work.

Affiliations

  1. Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Rd, Suzhou, 215004, China

    Zhiyuan Qian, Jiawei Ma, Yanping Xue, Yujun Xi, Lei Hong, Xiaoyan Ji, Yanming Chen, Minfeng Sheng, Yujing Sheng, Lin Yang, Jiachi Liu, Xingliang Dai, Jia Shi, Tao Xie & Jun Dong

  2. Department of Neurosurgery, Clinical Medical College of Yangzhou University, 98 Nantong West-Road, Yangzhou, 225001, China

    Yuping Li

  3. Department of Pathology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Rd, Suzhou, 215004, China

    Xiaoxiao Dai & Yongsheng Zhang

  4. Brain Tumor Lab, Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Soochow University, 1055 Sanxiang Rd, Suzhou, 215004, China

    Yujun Xi & Jun Dong

Authors
  1. Zhiyuan Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuping Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiawei Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanping Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yujun Xi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lei Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaoxiao Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yongsheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaoyan Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yanming Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Minfeng Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yujing Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Lin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jiachi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xingliang Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jia Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Tao Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Jun Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun Dong.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Qian, Z., Li, Y., Ma, J. et al. Prognostic value of NUSAP1 in progression and expansion of glioblastoma multiforme. J Neurooncol 140, 199–208 (2018). https://doi.org/10.1007/s11060-018-2942-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-018-2942-1

Keywords

  • NUSAP1
  • Glioblastoma multiforme
  • Survival
  • Prognostic factor