Skip to main content
Log in

Downregulation of N-Myc downstream-regulated gene 4 influences patient survival in gliomas

  • Original Article
  • Published:
Brain Tumor Pathology Aims and scope Submit manuscript

Abstract

N-Myc downstream-regulated gene 4 (NDRG4) plays important roles in cellular differentiation and neurite formation. It is required for cell cycle progression and survival in established glioblastoma cell lines and cancer stem cell-enriched cells. The aim of this study was to evaluate the correlation of NDRG4 expression with the clinicopathological features and prognosis in patients with gliomas. Immunohistochemistry and Western blot analysis were used to investigate the expression of NDRG4 protein, respectively, in 128 patients with gliomas. Immunohistochemistry showed that NDRG4 expression was significantly reduced in glioma relative to nonneoplastic brain tissues (P = 0.008), and that its expression decreased with increasing glioma grade. These results were in line with the results of Western blot analysis. In addition, a non-parametric analysis revealed that the reduced NDRG4 expression was significantly correlated with a low Karnofsky performance score (P = 0.01), frequent intra-tumor necrosis (P = 0.03), and poor overall survival (P = 0.01). Furthermore, multivariate analysis showed that NDRG4 expression (P = 0.03) and intra-tumor necrosis (P = 0.03) were two important independent prognostic factors identified by the Cox proportional hazard model. Our results provide convincing evidence for the first time that the expression of NDRG4 is downregulated in human gliomas. The glioma patients with lower NDRG4 expression have a poor prognosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Louis DN, Ohgaki H, Wiestler OD (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109

    Article  PubMed  Google Scholar 

  2. Shankavaram UT, Bredel M, Burgan WE, Carter D, Tofilon P, Camphausen K (2011) Molecular profiling indicates orthotopic xenograft of glioma cell lines simulate a subclass of human glioblastoma. J Cell Mol Med (in press)

  3. Liu X, Tang H, Zhang Z, Li W, Wang Z, Zheng Y, Wu M, Li G (2011) POTEH hypomethylation, a new epigenetic biomarker for glioma prognosis. Brain Res 1391:125–131

    Article  PubMed  CAS  Google Scholar 

  4. Melotte V, Qu X, Ongenaert M, van Criekinge W, de Bruïne AP, Baldwin HS, van Engeland M (2010) The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications. FASEB J 24:4153–4166

    Article  PubMed  CAS  Google Scholar 

  5. Shen L, Zhao ZY, Wang YZ, Ji SP, Liu XP, Liu XW, Che HL, Lin W, Li X, Zhang J, Yao LB (2008) Immunohistochemical detection of Ndrg2 in the mouse nervous system. Neuroreport 19:927–931

    Article  PubMed  CAS  Google Scholar 

  6. Qu X, Zhai Y, Wei H, Zhang C, Xing G, Yu Y, He F (2002) Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family. Mol Cell Biochem 229:35–44

    Article  PubMed  CAS  Google Scholar 

  7. Zhou RH, Kokame K, Tsukamoto Y, Yutani C, Kato H, Miyata T (2001) Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. Genomics 73:86–97

    Article  PubMed  CAS  Google Scholar 

  8. Yamamoto H, Kokame K, Okuda T, Nakajo Y, Yanamoto H, Miyata T (2011) NDRG4 protein-deficient mice exhibit spatial learning deficits and vulnerabilities to cerebral ischemia. J Biol Chem 286:26158–26165

    Article  PubMed  CAS  Google Scholar 

  9. Wang JF, Hill DJ (2009) Identification and action of N-myc downstream regulated gene 4 A2 in rat pancreas. J Endocrinol 201:15–25

    Article  PubMed  CAS  Google Scholar 

  10. Melotte V, Lentjes MH, van den Bosch SM, Hellebrekers DM, de Hoon JP, Wouters KA, Daenen KL, Partouns-Hendriks IE, Stessels F, Louwagie J, Smits KM, Weijenberg MP, Sanduleanu S, Khalid-de Bakker CA, Oort FA, Meijer GA, Jonkers DM, Herman JG, de Bruïne AP, van Engeland M (2009) N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst 101:916–927

    Article  PubMed  CAS  Google Scholar 

  11. Schilling SH, Hjelmeland AB, Radiloff DR, Liu IM, Wakeman TP, Fielhauer JR, Foster EH, Lathia JD, Rich JN, Wang XF, Datto MB (2009) NDRG4 is required for cell cycle progression and survival in glioblastoma cells. J Biol Chem 284:25160–25169

    Article  PubMed  CAS  Google Scholar 

  12. Kramm CM, Wagner S, Van Gool S, Schmid H, Sträter R, Gnekow A, Rutkowski S, Wolff JE (2006) Improved survival after gross total resection of malignant gliomas in pediatric patients from the HIT-GBM studies. Anticancer Res 26:3773–3779

    PubMed  Google Scholar 

  13. Bradford MM (1976) Rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  14. Yao L, Zhang J, Liu X (2008) NDRG2: a Myc-repressed gene involved in cancer and cell stress. Acta Biochim Biophys Sin (Shanghai) 40:625–635

    Article  CAS  Google Scholar 

  15. Nakada N, Hongo S, Ohki T, Maeda A, Takeda M (2002) Molecular characterization of NDRG4/Bdm1 protein isoforms that are differentially regulated during rat brain development. Brain Res Dev Brain Res 135:45–53

    Article  PubMed  CAS  Google Scholar 

  16. Ohki T, Hongo S, Nakada N, Maeda A, Takeda M (2002) Inhibition of neurite outgrowth by reduced level of NDRG4 protein in antisense transfected PC12 cells. Brain Res Dev Brain Res 135:55–63

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yang Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, S., Yang, B., Li, G. et al. Downregulation of N-Myc downstream-regulated gene 4 influences patient survival in gliomas. Brain Tumor Pathol 30, 8–14 (2013). https://doi.org/10.1007/s10014-012-0092-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10014-012-0092-2

Keywords

Navigation