Skip to main content
SpringerLink
Log in

Up-regulation of EphA2 and down-regulation of EphrinA1 are associated with the aggressive phenotype and poor prognosis of malignant glioma

  • Research Article
  • Published:
Tumor Biology

Abstract

Malignant gliomas display over-expression of the receptor tyrosine kinase EphA2. However, expression levels of the EphA2 ligand, EphrinA1, have not been fully elucidated. Seventy-eight patients with primary gliomas were included in this study who underwent surgical resection, radiation, and chemotherapy. The expression of EphA2 and EphrinA1 in tumors was assessed by immunohistochemistry and was statistically analyzed in combination with the follow-up data of patients. EphA2 was highly expressed in most malignant gliomas, but EphrinA1 was expressed at low levels in these tumors. The increased EphA2 expression is associated with higher-grade histology and poor patient prognosis. Contrary to this, the increased EphrinA1 expression is associated with lower-grade histology, but not associated with poor patient prognosis. Moreover, patients with tumors positive for EphA2 and negative for EphrinA1 had significantly shorter overall and progression-free survival than patients with tumors positive for both EphA2 and EphrinA1, negative for both EphA2 and EphrinA1, or negative for EphA2 and positive for EphrinA1. RNAi-mediated suppression of endogenous EphA2 in human glioblastoma multiforme cells resulted in increased EphrinA1 levels, as well as decreased cell viability, anchorage independence and in vitro invasion, and increased apoptosis. Furthermore, suppression of EphA2 resulted in delayed tumor growth in mice xenografts. Together, these data indicate that up-regulation of EphA2 and down-regulation of Ephrina1 may correlate with poor prognosis for patients with high-grade glioma. EphA2 suppression partially reversed the aggressive phenotypes of malignant gliomas, possibly through up-regulating EphrinA1 expression, which may help explain how EphA2 modulates the malignant progression of gliomas.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Kleihues P, Cavenee WK. World health organization classification of tumours: pathology and genetics of tumours of the nervous system. Lyon: IARC; 2000.

    Google Scholar 

  2. Lindberg RA, Hunter T. cDNA cloning and characterization of eck, an epithelial cell receptor protein-tyrosine kinase in the eph/elk family of protein kinases. Mol Cell Biol. 1990;10:6316–24.

    CAS  PubMed  Google Scholar 

  3. Sulman EP, Tang XX, Allen C, Biegel JA, Pleasure DE, Brodeur GM, et al. ECK, a human EPH-related gene, maps to 1p36.1, a common region of alteration in human cancers. Genomics. 1997;40:371–4.

    Article  CAS  PubMed  Google Scholar 

  4. Kinch MS, Moore MB, Harpole Jr DH. Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival. Clin Cancer Res. 2003;9:613–8.

    CAS  PubMed  Google Scholar 

  5. Noblitt LW, Bangari DS, Shukla S, Knapp DW, Mohammed S, Kinch MS, et al. Decreased tumorigenic potential of EphA2-overexpressing breast cancer cells following treatment with adenoviral vectors that express EphrinA1. Cancer Gene Ther. 2004;11:757–66.

    Article  CAS  PubMed  Google Scholar 

  6. Abraham S, Knapp DW, Cheng L, Snyder PW, Mittal SK, Bangari DS, et al. Expression of EphA2 and Ephrin A-1 in carcinoma of the urinary bladder. Clin Cancer Res. 2006;12:353–60.

    Article  CAS  PubMed  Google Scholar 

  7. Nakamura R, Kataoka H, Sato N, Kanamori M, Ihara M, Igarashi H, et al. EPHA2/EFNA1 expression in human gastric cancer. Cancer Sci. 2005;96:42–7.

    Article  CAS  PubMed  Google Scholar 

  8. Kataoka H, Igarashi H, Kanamori M, Ihara M, Wang JD, Wang YJ, et al. Correlation of EPHA2 overexpression with high microvessel count in human primary colorectal cancer. Cancer Sci. 2004;95:136–41.

    Article  CAS  PubMed  Google Scholar 

  9. Walker-Daniels J, Coffman K, Azimi M, Rhim JS, Bostwick DG, Snyder P, et al. Overexpression of the EphA2 tyrosine kinase in prostate cancer. Prostate. 1999;41:275–80.

    Article  CAS  PubMed  Google Scholar 

  10. Landen CN, Kinch MS, Sood AK. EphA2 as a target for ovarian cancer therapy. Expert Opin Ther Targets. 2005;9:1179–87.

    Article  CAS  PubMed  Google Scholar 

  11. Herrem CJ, Tatsumi T, Olson KS, Shirai K, Finke JH, Bukowski RM, et al. Expression of EphA2 is prognostic of disease-free interval and overall survival in surgically treated patients with renal cell carcinoma. Clin Cancer Res. 2005;11:226–31.

    CAS  PubMed  Google Scholar 

  12. Xu F, Zhong W, Li J, Shanshen Z, Cui J, Nesland JM, et al. Predictive value of EphA2 and EphrinA-1 expression in oesophageal squamous cell carcinoma. Anticancer Res. 2005;25:2943–50.

    CAS  PubMed  Google Scholar 

  13. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma. Oncogene. 2004;23:1448–56.

    Article  CAS  PubMed  Google Scholar 

  14. Easty DJ, Hill SP, Hsu MY, Fallowfield ME, Florenes VA, Herlyn M, et al. Up-regulation of ephrin-A1 during melanoma progression. Int J Cancer. 1999;84:494–501.

    Article  CAS  PubMed  Google Scholar 

  15. Holzman LB, Marks RM, Dixit VM. A novel immediate-early response gene of endothelium is induced by cytokines and encodes a secreted protein. Mol Cell Biol. 1990;10:5830–8.

    CAS  PubMed  Google Scholar 

  16. Carles-Kinch K, Kilpatrick KE, Stewart JC, Kinch MS. Antibody targeting of the EphA2 tyrosine kinase inhibits malignant cell behavior. Cancer Res. 2002;62:2840–7.

    CAS  PubMed  Google Scholar 

  17. Miao H, Wei BR, Peehl DM, Li Q, Alexandrou T, Schelling JR, et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat Cell Biol. 2001;3:527–30.

    Article  CAS  PubMed  Google Scholar 

  18. Zantek ND, Azimi M, Fedor-Chaiken M, Wang B, Brackenbury R, Kinch MS. E-cadherin regulates the function of the EphA2 receptor tyrosine kinase. Cell Growth Differ. 1999;10:629–38.

    CAS  PubMed  Google Scholar 

  19. Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res. 2001;61:2301–6.

    CAS  PubMed  Google Scholar 

  20. Han L, Dong Z, Qiao Y, Kristensen GB, Holm R, Nesland JM, et al. The clinical significance of EphA2 and Ephrin A-1 in epithelial ovarian carcinomas. Gynecol Oncol. 2005;99:278–86.

    Article  CAS  PubMed  Google Scholar 

  21. Wu D, Suo Z, Kristensen GB, Li S, Troen G, Holm R, et al. Prognostic value of EphA2 and EphrinA-1 in squamous cell cervical carcinoma. Gynecol Oncol. 2004;94:312–9.

    Article  CAS  PubMed  Google Scholar 

  22. Hatano M, Eguchi J, Tatsumi T, Kuwashima N, Dusak JE, Kinch MS, et al. EphA2 as a glioma-associated antigen: a novel target for glioma vaccines. Neoplasia. 2005;7:717–22.

    Article  CAS  PubMed  Google Scholar 

  23. Li X, Wang Y, Wang Y, Zhen H, Yang H, Fei Z, et al. Expression of EphA2 in human astrocytic tumors: correlation with pathologic grade, proliferation and apoptosis. Tumour Biol. 2007;28:165–72.

    Article  PubMed  Google Scholar 

  24. Liu F, Park PJ, Lai W, Maher E, Chakravarti A, Durso L, et al. A genome-wide screen reveals functional gene clusters in the cancer genome and identifies EphA2 as a mitogen in glioblastoma. Cancer Res. 2006;66:10815–23.

    Article  CAS  PubMed  Google Scholar 

  25. Wang LF, Fokas E, Bieker M, Rose F, Rexin P, Zhu Y, et al. Increased expression of EphA2 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients. Oncol Rep. 2008;19:151–6.

    PubMed  Google Scholar 

  26. Zhou Z, Yuan X, Li Z, Tu H, Li D, Qing J, et al. RNA interference targeting EphA2 inhibits proliferation, induces apoptosis, and cooperates with cytotoxic drugs in human glioma cells. Surg Neurol. 2008;70:562–8.

    Article  PubMed  Google Scholar 

  27. Frisch SM, Vuori K, Ruoslahti E, Chan-Hui PY. Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol. 1996;134:793–9.

    Article  CAS  PubMed  Google Scholar 

  28. Carter N, Nakamoto T, Hirai H, Hunter T. EphrinA1-induced cytoskeletal re-organization requires FAK and p130(cas). Nat Cell Biol. 2002;4:565–73.

    CAS  PubMed  Google Scholar 

  29. Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. Ligation of EphA2 by Ephrin A1-Fc inhibits pancreatic adenocarcinoma cellular invasiveness. Biochem Biophys Res Commun. 2004;320:1096–102.

    Article  CAS  PubMed  Google Scholar 

  30. Liu DP, Wang Y, Koeffler HP, Xie D. Ephrin-A1 is a negative regulator in glioma through down-reguation of EphA2 and FAK. Int J Oncol. 2007;30:865–71.

    CAS  PubMed  Google Scholar 

  31. Wykosky J, Debinski W. The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting. Mol Cancer Res. 2008;6:1795–806.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Harry C. Wang (Nastech Pharmaceutical Company Inc., USA) for revising the language of this manuscript.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shaan Xi Province, People’s Republic of China

    Xia Li, Bing Li, Wei-Ping Liu, Yan-Gang Wang, Xiang Zhang, Hai-Ning Zhen & Zhou Fei

  2. Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, People’s Republic of China

    Li Wang

  3. Department of Neurosurgery, General Hospital of Chengdu Military Region of PLA, Chengdu, 610083, People’s Republic of China

    Jian-Wen Gu

Authors
  1. Xia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jian-Wen Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei-Ping Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yan-Gang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hai-Ning Zhen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhou Fei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhou Fei.

Additional information

Xia Li, Li Wang, and Jian-Wen Gu contributed equally to this paper.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, X., Wang, L., Gu, JW. et al. Up-regulation of EphA2 and down-regulation of EphrinA1 are associated with the aggressive phenotype and poor prognosis of malignant glioma. Tumor Biol. 31, 477–488 (2010). https://doi.org/10.1007/s13277-010-0060-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-010-0060-6

Keywords

Search

Navigation