High Cytoplasmic Expression of the Orphan Nuclear Receptor NR4A2 Predicts Poor Survival in Nasopharyngeal Carcinoma

  • Wang, Jian (Sino-American Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical College) ;
  • Yang, Jing (Department of Biochemistry, Liaoning Medical College) ;
  • Li, Bin-Bin (Sino-American Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical College) ;
  • He, Zhi-Wei (Sino-American Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical College)
  • Published : 2013.05.30


Objective: This study aimed at investigating whether the orphan nuclear receptor NR4A2 is significantly associated with clinicopathologic features and overall survival of patients with nasopharyngeal carcinoma (NPC). Methods: Immunohistochemistry was performed to determine NR4A2 protein expression in 84 NPC tissues and 20 non-cancerous nasopharyngeal (NP) tissues. The prognostic significance of NR4A2 protein expression was evaluated using Cox proportional hazards regression models and Kaplan-Meier survival analysis. Results: We did not find a significant association between total NR4A2 expression and clinicopathological variables in 84 patients with NPC. However, we observed that high cytoplasmic expression of NR4A2 was significantly associated with tumor size (T classification) (P = 0.006), lymph node metastasis (N classification) (P = 0.002) and clinical stage (P = 0.017). Patients with higher cytoplasmic NR4A2 expression had a significantly lower survival rate than those with lower cytoplasmic NR4A2 expression (P = 0.004). Multivariate Cox regression analysis analysis suggested that the level of cytoplasmic NR4A2 expression was an independent prognostic indicator for overall survival of patients with NPC (P = 0.033). Conclusions: High cytoplasmic expression of NR4A2 is a potential unfavorable prognostic factor for patients with NPC.


  1. Acikalin MF, Etiz D, Gurbuz MK, et al (2012). Prognostic significance of galectin-3 and cyclin D1 expression in undifferentiated nasopharyngeal carcinoma. Med Oncol, 29, 742-9.
  2. Brennan B (2006). Nasopharyngeal carcinoma. Orphanet J Rare Dis, 1, 23.
  3. Ben Nasr H, Chahed K, Remadi S, Zakhama A, Chouchane L (2009). Expression and clinical significance of latent membrane protein-1, matrix metalloproteinase-1 and Ets-1 transcription factor in tunisian nasopharyngeal carcinoma patients. Arch Med Res, 40, 196-203.
  4. Bonta PI, Pols TW, van Tiel CM, et al (2010). Nuclear receptor Nurr1 is expressed in and is associated with human restenosis and inhibits vascular lesion formation in mice involving inhibition of smooth muscle cell proliferation and inflammation. Circulation, 121, 2023-32.
  5. Chua DT, Ma J, Sham JS, et al (2005). Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials. J Clin Oncol, 23, 1118-24.
  6. Chan AT (2010). Nasopharyngeal carcinoma. Ann Oncol, 21, 308-12.
  7. Cao XJ, Hao JF, Yang XH, et al (2012). Prognostic value of expression of EGFR and nm23 for locoregionally advanced nasopharyngeal carcinoma. Med Oncol, 29, 263-71.
  8. Deutsch AJ, Angerer H, Fuchs TE, Neumeister P (2012). The nuclear orphan receptors NR4A as therapeutic target in cancer therapy. Anticancer Agents Med Chem, 12, 1001-14.
  9. Holla VR, Mann JR, Shi Q, DuBois RN (2006). Prostaglandin E2 regulates the nuclear receptor NR4A2 in colorectal cancer. J Biol Chem, 281, 2676-82.
  10. Inamoto T, Czerniak BA, Dinney CP, Kamat AM (2010). Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer. Cancer, 116, 340-6.
  11. Ke N, Claassen G, Yu DH, et al (2004). Nuclear hormone receptor NR4A2 is involved in cell transformation and apoptosis. Cancer Res, 64, 8208-12.
  12. Kitagawa N, Kondo S, Wakisaka N, et al (2013). Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: Novel prognostic factors of nasopharyngeal carcinoma. Cancer Lett, 331, 52-7.
  13. Li H, Kolluri SK, Gu J, et al (2000). Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science, 289, 1159-64.
  14. Lin B, Kolluri SK, Lin F, et al (2004). Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell, 116, 527-40.
  15. Li XM, Huang WG, Yi H, Cheng AL, Xiao ZQ (2009). Proteomic analysis to identify cytokeratin 18 as a novel biomarker of nasopharyngeal carcinoma. J Cancer Res Clin Oncol, 135, 1763-75.
  16. Li X, Tai HH (2009). Activation of thromboxane A2 receptors induces orphan nuclear receptor Nurr1 expression and stimulates cell proliferation in human lung cancer cells. Carcinogenesis, 30, 1606-13.
  17. Lee HS, Bae EJ, Yi SH, et al (2010). Foxa2 and Nurr1 synergistically yield A9 nigral dopamine neurons exhibiting improved differentiation, function, and cell survival. Stem Cells, 28, 501-12.
  18. Maijenburg MW, Gilissen C, Melief SM, et al (2012). Nuclear receptors Nur77 and Nurr1 modulate mesenchymal stromal cell migration. Stem Cells Dev, 21, 228-38.
  19. Razak AR, Siu LL, Liu FF, et al (2010). Nasopharyngeal carcinoma: the next challenges. Eur J Cancer, 46, 1967-78.
  20. Sirin O, Lukov GL, Mao R, Conneely OM, Goodell MA (2010). The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells. Nat Cell Biol, 12, 1213-9.
  21. Zhang T, Wang P, Ren H, Fan J, Wang G (2009). NGFI-B nuclear orphan receptor Nurr1 interacts with p53 and suppresses its transcriptional activity. Mol Cancer Res, 7, 1408-15.
  22. Zhou J, Xiao X, Yi H, et al (2012). Upregulation of Gp96 correlates with the radiosensitivity and five-year survival rate of nasopharyngeal carcinoma. ORL J Otorhinolaryngol Relat Spec, 74, 164-71.

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