Expression and prognosis of FOXO3a and HIF-1α in nasopharyngeal carcinoma

  • Zhu Shou
  • Li Lin
  • Jia Liang
  • Jing-Li Li
  • Hong-Yan Chen
Original Paper



The Forkhead Box O3a transcription factor (FOXO3a) and hypoxia-inducible factor-1α (HIF-1α) have been reported to play important roles in the development and prognosis of human cancers. However, their exact roles are not clear. Therefore, we investigated the expression status and clinical significance of FOXO3a and HIF-1α expression in nasopharyngeal carcinoma.


The expression of FOXO3a and HIF-1α proteins was detected in nasopharyngeal carcinoma tissues and normal nasopharyngeal tissues by immunohistochemistry and western blot. Furthermore, we analyzed the association of FOXO3a and HIF-1α expression with various clinicopathologic factors including survival status of nasopharyngeal carcinoma patients.


FOXO3a was low expressed and HIF-1α was high expressed in nasopharyngeal carcinoma tissues, compared with normal nasopharyngeal tissues (both P < 0.05). The low expression of FOXO3a was significantly correlated with clinical stage (P = 0.003), T stage (P = 0.011), lymph node metastasis (P = 0.003), and distant metastasis (P = 0.030), and over expression of HIF-1α was significantly correlated with T stage (P = 0.026), lymph node metastasis (P = 0.002), and distant metastasis (P = 0.010). The Spearman analysis indicated that FOXO3a expression was inversely correlated with HIF-1α expression(rs = −0.598, P < 0.001). Overall survival curves estimated by Kaplan–Meier showed that tumor patients with low FOXO3a or high HIF-1α expression had significantly poorer prognosis compared with patients with high FOXO3a or low HIF-1α levels (P < 0.001, and P = 0.012, respectively). In addition, multivariate Cox regression analysis showed that T stage, distant metastasis, and FOXO3a were significant independent prognostic factors for overall survival (P = 0.011, P = 0.008, and P = 0.047, respectively).


Our results suggested that FOXO3a and HIF-1α may be considered to be important prognostic markers in nasopharyngeal carcinoma.


Nasopharyngeal carcinoma FOXO3a HIF-1α Immunohistochemistry Prognosis 


  1. Accili D, Arden KC (2004) FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117(4):421–426PubMedCrossRefGoogle Scholar
  2. Bakker WJ, Harris IS, Mak TW (2007) FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Mol Cell 28(6):941–953. doi:10.1016/j.molcel.2007.10.035 PubMedCrossRefGoogle Scholar
  3. Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, Dewhirst MW (1996) Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 56(5):941–943PubMedGoogle Scholar
  4. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6):857–868PubMedCrossRefGoogle Scholar
  5. Burgering BM, Kops GJ (2002) Cell cycle and death control: long live Forkheads. Trends Biochem Sci 27(7):352–360PubMedCrossRefGoogle Scholar
  6. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394(6692):485–490. doi:10.1038/28867 PubMedCrossRefGoogle Scholar
  7. Chiacchiera F, Matrone A, Ferrari E, Ingravallo G, Lo Sasso G, Murzilli S, Petruzzelli M, Salvatore L, Moschetta A, Simone C (2009) p38α blockade inhibits colorectal cancer growth in vivo by inducing a switch from HIF1α- to FoxO-dependent transcription. Cell Death Differ 16(9):1203–1214. doi:10.1038/cdd.2009.36 PubMedCrossRefGoogle Scholar
  8. Chua DT, Ma J, Sham JS, Mai HQ, Choy DT, Hong MH, Lu TX, Min HQ (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(6):1118–1124. doi:10.1200/jco.2005.12.081 PubMedCrossRefGoogle Scholar
  9. Emerling BM, Weinberg F, Liu JL, Mak TW, Chandel NS (2008) PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci 105(7):2622–2627. doi:10.1073/pnas.0706790105 PubMedCrossRefGoogle Scholar
  10. Fang L, Wang H, Zhou L, Yu D (2011) Akt-FOXO3a signaling axis dysregulation in human oral squamous cell carcinoma and potent efficacy of FOXO3a-targeted gene therapy. Oral Oncol 47(1):16–21. doi:10.1016/j.oraloncology.2010.10.010 PubMedCrossRefGoogle Scholar
  11. Fei M, Zhao Y, Wang Y, Lu M, Cheng C, Huang X, Zhang D, Lu J, He S, Shen A (2009) Low expression of Foxo3a is associated with poor prognosis in ovarian cancer patients. Cancer Investig 27(1):52–59. doi:10.1080/07357900802146204 CrossRefGoogle Scholar
  12. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC (1953) The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 26(312):638–648PubMedCrossRefGoogle Scholar
  13. Habashy HO, Rakha EA, Aleskandarany M, Ahmed MA, Green AR, Ellis IO, Powe DG (2011) FOXO3a nuclear localisation is associated with good prognosis in luminal-like breast cancer. Breast Cancer Res Treat 129(1):11–21. doi:10.1007/s10549-010-1161-z PubMedCrossRefGoogle Scholar
  14. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P (1996) Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56(19):4509–4515PubMedGoogle Scholar
  15. Hong MH, Mai HQ, Min HQ, Ma J, Zhang EP, Cui NJ (2000) A comparison of the Chinese 1992 and fifth-edition international union against cancer staging systems for staging nasopharyngeal carcinoma. Cancer 89(2):242–247PubMedCrossRefGoogle Scholar
  16. Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, Zou Y, Bao S, Hanada N, Saso H, Kobayashi R, Hung MC (2004) IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117(2):225–237PubMedCrossRefGoogle Scholar
  17. Hui EP, Chan AT, Pezzella F, Turley H, To KF, Poon TC, Zee B, Mo F, Teo PM, Huang DP, Gatter KC, Johnson PJ, Harris AL (2002) Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin Cancer Res 8(8):2595–2604PubMedGoogle Scholar
  18. Jia WH, Huang QH, Liao J, Ye W, Shugart YY, Liu Q, Chen LZ, Li YH, Lin X, Wen FL, Adami HO, Zeng Y, Zeng YX (2006) Trends in incidence and mortality of nasopharyngeal carcinoma over a 20–25 year period (1978/1983–2002) in Sihui and Cangwu counties in southern China. BMC Cancer 6:178. doi:10.1186/1471-2407-6-178 PubMedCrossRefGoogle Scholar
  19. Jiang BH, Jiang G, Zheng JZ, Lu Z, Hunter T, Vogt PK (2001) Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ 12(7):363–369PubMedGoogle Scholar
  20. Karger S, Weidinger C, Krause K, Sheu SY, Aigner T, Gimm O, Schmid KW, Dralle H, Fuhrer D (2008) FOXO3a: a novel player in thyroid carcinogenesis? Endocr Relat Cancer 16(1):189–199. doi:10.1677/erc-07-0283 PubMedCrossRefGoogle Scholar
  21. Koh MY, Spivak-Kroizman TR, Powis G (2010) HIF-1alpha and cancer therapy. Recent Results Cancer Res 180:15–34. doi:10.1007/978-3-540-78281-0_3 PubMedCrossRefGoogle Scholar
  22. Lu M, Ma J, Xue W, Cheng C, Wang Y, Zhao Y, Ke Q, Liu H, Liu Y, Li P, Cui X, He S, Shen A (2009) The expression and prognosis of FOXO3a and Skp2 in human hepatocellular carcinoma. Pathol Oncol Res 15(4):679–687. doi:10.1007/s12253-009-9171-z PubMedCrossRefGoogle Scholar
  23. Rankin EB, Giaccia AJ (2008) The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 15(4):678–685. doi:10.1038/cdd.2008.21 PubMedCrossRefGoogle Scholar
  24. Semenza GL (2000) Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 35(2):71–103. doi:10.1080/10409230091169186 PubMedCrossRefGoogle Scholar
  25. Shi J, Zhang L, Shen A, Zhang J, Wang Y, Zhao Y, Zou L, Ke Q, He F, Wang P, Cheng C, Shi G (2009) Clinical and biological significance of forkhead class box O 3a expression in glioma: mediation of glioma malignancy by transcriptional regulation of p27kip1. J Neuro-Oncol 98(1):57–69. doi:10.1007/s11060-009-0045-8 CrossRefGoogle Scholar
  26. Shiota M, Song Y, Yokomizo A, Kiyoshima K, Tada Y, Uchino H, Uchiumi T, Inokuchi J, Oda Y, Kuroiwa K, Tatsugami K, Naito S (2010) Foxo3a suppression of urothelial cancer invasiveness through Twist1, Y-box-binding protein 1, and E-cadherin regulation. Clin Cancer Res 16(23):5654–5663. doi:10.1158/1078-0432.ccr-10-0376 PubMedCrossRefGoogle Scholar
  27. Shukla S, Shukla M, Maclennan GT, Fu P, Gupta S (2009) Deregulation of FOXO3A during prostate cancer progression. Int J Oncol 34(6):1613–1620PubMedGoogle Scholar
  28. Taylor CR (2006) Quantifiable internal reference standards for immunohistochemistry: the measurement of quantity by weight. Appl Immunohistochem Mol Morphol 14(3):253–259PubMedCrossRefGoogle Scholar
  29. Tran H, Brunet A, Griffith EC, Greenberg ME (2003) The many forks in FOXO’s road. Sci STKE (172):RE5. doi:10.1126/stke.2003.172.re5
  30. Xueguan L, Xiaoshen W, Yongsheng Z, Chaosu H, Chunying S, Yan F (2008) Hypoxia inducible factor-1 alpha and vascular endothelial growth factor expression are associated with a poor prognosis in patients with nasopharyngeal carcinoma receiving radiotherapy with carbogen and nicotinamide. Clin Oncol (R Coll Radiol) 20(8):606–612. doi:10.1016/j.clon.2008.07.001 CrossRefGoogle Scholar
  31. Yu MC, Yuan JM (2002) Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol 12(6):421–429PubMedCrossRefGoogle Scholar
  32. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59(22):5830–5835PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Zhu Shou
    • 1
  • Li Lin
    • 1
  • Jia Liang
    • 1
  • Jing-Li Li
    • 1
  • Hong-Yan Chen
    • 1
  1. 1.Department of OtolaryngologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingPeople’s Republic of China

Personalised recommendations