SpringerLink
Log in

Diagnostic and prognostic value of tissue and circulating levels of Ephrin-A2 in prostate cancer

  • Original Article
  • Published:
Tumor Biology

Abstract

Ephrin-A2, a member of the Eph/ephrin family, is associated with tumorigenesis and tumor progression. This study aimed to assess the diagnostic and prognostic value of both serum and tissue levels of Ephrin-A2 in prostate cancer (PCa) management. One hundred and forty-five frozen prostate tissues, 55 paraffin-embedded prostate tissues, 88 serum samples, and seven prostate cell lines (RWPE-1, LNCaP, LNCaP-LN3, PC-3, PC-3M, PC-3M-LN4, and DU145) were examined via quantitative reverse transcription-PCR (qRT-PCR), immunohistochemistry, enzyme-linked immunosorbent assay, and western blotting. Induced Ephrin-A2 messenger RNA (mRNA) or protein expression was detected in 8.6 % (5/58) benign prostatic hyperplasia (BPH), 59.8 % (52/87) PCa, and five prostate cancer cell lines. Ephrin-A2 immunostaining was present in 6.7 % (1/15) patients with BPHs and 62.5 % (25/40) clinically localized PCa. Accordingly, serum Ephrin-A2 was significantly higher in PCa patients compared to those in the BPH patients and controls (P < 0.001). The expression of Ephrin-A2 was higher in tumor patients with an elevated Gleason score or T3–T4 staging. Ephrin-A2 expression was correlated with Ki-67 expression in PCa patients, both at the gene scale and protein level. Our data indicate that Ephrin-A2 is a potential diagnostic and prognostic biomarker and a promising molecular therapeutic target to attenuate prostate cancer progression.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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. Smith RA, Manassaram-Baptiste D, Brooks D, Cokkinides V, Doroshenk M, Saslow D, et al. Cancer screening in the United States, 2014: a review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin. 2014;64:30–51.

    Article  PubMed  Google Scholar 

  2. Gu F. Changing constituents of genitourinary cancer in recent 50 years in Bei**g. Chin Med J (Engl). 2003;116:1391–3.

    Google Scholar 

  3. Dimakakos A, Armakolas A, Koutsilieris M. Novel tools for prostate cancer prognosis, diagnosis, and follow-up. Biomed Res Int. 2014;2014:890697.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lilja H, Ulmert D, Vickers AJ. Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer. 2008;8:268–78.

    Article  CAS  PubMed  Google Scholar 

  5. Diamandis EP. Prostate-specific antigen: its usefulness in clinical medicine. Trends Endocrinol Metab. 1998;9:310–6.

    Article  CAS  PubMed  Google Scholar 

  6. Lisabeth EM, Falivelli G, Pasquale EB. Eph receptor signaling and ephrins. Cold Spring Harb Perspect Biol. 2013;5:9.

    Article  Google Scholar 

  7. Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer. 2010;10:165–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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 

  9. Ogawa K, Pasqualini R, Lindberg RA, Kain R, Freeman AL, Pasquale EB. The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene. 2000;19:6043–52.

    Article  CAS  PubMed  Google Scholar 

  10. Thaker PH, Deavers M, Celestino J, Thornton A, Fletcher MS, Landen CN, et al. EphA2 expression is associated with aggressive features in ovarian carcinoma. Clin Cancer Res. 2004;10:5145–50.

    Article  CAS  PubMed  Google Scholar 

  11. Taddei ML, Parri M, Angelucci A. EphA2 induces metastatic growth regulating amoeboid motility and clonogenic potential in prostate carcinoma cells. Mol Cancer Res. 2011;9:149–60.

    Article  CAS  PubMed  Google Scholar 

  12. Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, et al. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009;16:9–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. **a G, Kumar SR, Masood R, Zhu S, Reddy R, Krasnoperov V, et al. EphB4 expression and biological significance in prostate cancer. Cancer Res. 2005;65:4623–32.

    Article  CAS  PubMed  Google Scholar 

  14. **a G, Kumar SR, Stein JP, Singh J, Krasnoperov V, Zhu S, et al. EphB4 receptor tyrosine kinase is expressed in bladder cancer and provides signals for cell survival. Oncogene. 2006;25:769–80.

    Article  CAS  PubMed  Google Scholar 

  15. Rutkowski R, Mertens-Walker I, Lisle JE, Herington AC, Stephenson SA. Evidence for a dual function of EphB4 as tumor promoter and suppressor regulated by the absence or presence of the ephrin-B2 ligand. Int J Cancer. 2012;131:E614–24.

    Article  CAS  PubMed  Google Scholar 

  16. Li S, Ma Y, **e C, Wu Z, Kang Z, Fang Z, et al. EphA6 promotes angiogenesis and prostate cancer metastasis and is associated with human prostate cancer progression. Oncotarget. 2015.

  17. Li S, Zhu Y, Ma C, Qiu Z, Zhang X, Kang Z, et al. Downregulation of EphA5 by promoter methylation in human prostate cancer. BMC Cancer. 2015;15:18.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Roberta N, Rubio Dela Torre E, Pasquale EB. Profiling Eph receptor expression in cells and tissues: a targeted mass spectrometry approach. Cell Adh Migr. 2012;6:102–12.

    Article  Google Scholar 

  19. Aasheim HC, Pedeutour F, Grosgeorge J, Logtenberg T. Cloning, chromosal map**, and tissue expression of the gene encoding the human Eph-family kinase ligand ephrin-A2. Biochem Biophys Res Commun. 1998;252:378–82.

    Article  CAS  PubMed  Google Scholar 

  20. Hafner C, Schmitz G, Meyer S, Bataille F, Hau P, Langmann T, et al. Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers. Clin Chem. 2004;50:490–9.

    Article  CAS  PubMed  Google Scholar 

  21. Feng YX, Zhao JS, Li JJ, Wang T, Cheng SQ, Yuan Y, et al. Liver cancer: EphrinA2 promotes tumorigenicity through Rac1/Akt/NF-kappaB signaling pathway. Hepatology. 2010;51:535–44.

    Article  CAS  PubMed  Google Scholar 

  22. Fox BP, Kandpal RP. Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application. Biochem Biophys Res Commun. 2004;318:882–92.

    Article  CAS  PubMed  Google Scholar 

  23. Fox BP, Tabone CJ, Kandpal RP. Potential clinical relevance of Eph receptors and ephrin ligands expressed in prostate carcinoma cell lines. Biochem Biophys Res Commun. 2006;342:1263–72.

    Article  CAS  PubMed  Google Scholar 

  24. Hattori M, Osterfield M, Flanagan JG. Regulated cleavage of a contact-mediated axon repellent. Science. 2000;289:1360–5.

    Article  CAS  PubMed  Google Scholar 

  25. Yates NJ, Martin-Iverson MT, Rodger J. The role of ephrin-A2 and ephrin-A5 in sensorimotor control and gating. Behav Brain Res. 2014;275:225–33.

    Article  CAS  PubMed  Google Scholar 

  26. Diercke K, Sen S, Kohl A, Lux CJ, Erber R. Compression-dependent up-regulation of ephrin-A2 in PDL fibroblasts attenuates osteogenesis. J Dent Res. 2011;90:1108–15.

    Article  CAS  PubMed  Google Scholar 

  27. Ornish D. Intensive lifestyle changes may affect the progression of prostate cancer. J Urol. 2005;174:1065–9.

    Article  PubMed  Google Scholar 

  28. Barry MJ. Evaluation of symptoms and quality of life in men with benign prostatic hyperplasia. Urology. 2001;58:25–32.

    Article  CAS  PubMed  Google Scholar 

  29. Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, et al. Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell. 2005;123:291–304.

    Article  CAS  PubMed  Google Scholar 

  30. Ieguchi K, Tomita T, Omori T, Komatsu A, Deguchi A, Masuda J, et al. ADAM12-cleaved ephrin-A1 contributes to lung metastasis. Oncogene. 2014;33:2179–90.

    Article  CAS  PubMed  Google Scholar 

  31. Wykosky J, Palma E, Gibo DM, Ringler S, Turner CP, Debinski W. Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor. Oncogene. 2008;27:7260–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cui XD, Lee MJ, Yu GR, Kim IH, Yu HC, Song EY, et al. EFNA1 ligand and its receptor EphA2: potential biomarkers for hepatocellular carcinoma. Int J Cancer. 2010;126:940–9.

    CAS  PubMed  Google Scholar 

  33. Kälin M, Cima I, Schiess R, Fankhauser N, Powles T, Wild P, et al. Novel prognostic markers in the serum of patients with castration-resistant prostate cancer derived from quantitative analysis of the pten conditional knockout mouse proteome. Eur Urol. 2011;60:1235–43.

    Article  PubMed  Google Scholar 

  34. Lisle JE, Mertens-Walker I, Rutkowski R, Herington AC, Stephenson SA. Eph receptors and their ligands: promising molecular biomarkers and therapeutic targets in prostate cancer. Biochim Biophys Acta. 1835;2013:243–57.

    Google Scholar 

  35. McCulloch DR, Akl P, Samaratunga H, Herington AC, Odorico DM. Expression of the disintegrin metalloprotease, ADAM-10, in prostate cancer and its regulation by dihydrotestosterone, insulin-like growth factor I, and epidermal growth factor in the prostate cancer cell model LNCaP. Clin Cancer Res. 2004;10:314–23.

    Article  CAS  PubMed  Google Scholar 

  36. Arima T, Enokida H, Kubo H, Kagara I, Matsuda R, Toki K, et al. Nuclear translocation of ADAM-10 contributes to the pathogenesis and progression of human prostate cancer. Cancer Sci. 2007;98:1720–6.

    Article  CAS  PubMed  Google Scholar 

  37. Li H, Han X, Liu Y, Liu G, Dong G. Ki67 as a predictor of poor prognosis in patients with triple-negative breast cancer. Oncol Lett. 2015;9:149–52.

    PubMed  Google Scholar 

  38. Berghoff AS, Ilhan-Mutlu A, Wöhrer A, Hackl M, Widhalm G, Hainfellner JA, et al. Prognostic significance of Ki67 proliferation index, HIF1 alpha index and microvascular density in patients with non-small cell lung cancer brain metastases. Strahlenther Onkol. 2014;190:676–85.

    Article  CAS  PubMed  Google Scholar 

  39. Salminen E, Palmu S, Vahlberg T, Roberts PJ, Söderström KO. Increased proliferation activity measured by immunoreactive Ki67 is associated with survival improvement in rectal/recto sigmoid cancer. World J Gastroenterol. 2005;11:3245–9.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Zellweger T, Günther S, Zlobec I, Savic S, Sauter G, Moch H, et al. Tumour growth fraction measured by immunohistochemical staining of Ki67 is an independent prognostic factor in preoperative prostate biopsies with small-volume or low-grade prostate cancer. Int J Cancer. 2009;124:2116–23.

    Article  CAS  PubMed  Google Scholar 

  41. Rubio J, Ramos D, López-Guerrero JA, Iborra I, Collado A, Solsona E, et al. Immunohistochemical expression of Ki-67 antigen, cox-2 and Bax/Bcl-2 in prostate cancer; prognostic value in biopsies and radical prostatectomy specimens. Eur Urol. 2005;48:745–51.

    Article  CAS  PubMed  Google Scholar 

  42. Pollack A, DeSilvio M, Khor LY, Li R, Al-Saleem TI, Hammond ME, et al. Ki-67 staining is a strong predictor of distant metastasis and mortality for men with prostate cancer treated with radiotherapy plus androgen deprivation: Radiation Therapy Oncology Group Trial 92–02. J Clin Oncol. 2004;22:2133–40.

    Article  CAS  PubMed  Google Scholar 

  43. Tomaszewski JJ, Cummings JL, Parwani AV, Dhir R, Mason JB, Nelson JB, et al. Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate. Prostate. 2011;71:1287–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Gunia S, Albrecht K, Koch S, Herrmann T, Ecke T, Loy V, et al. Ki67 staining index and neuroendocrine differentiation aggravate adverse prognostic parameters in prostate cancer and are characterized by negligible inter-observer variability. World J Urol. 2008;26:243–50.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by the National Natural Science Foundation of China (No. 81272386), the Shanghai Municipal Health Bureau Hundred Talents Program (XBR2011044), and the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20120071110073). We gratefully acknowledge the Nature Publishing Group Language Editing for linguistic assistance in manuscript preparation.

Author information

Author notes

    Authors and Affiliations

    1. Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical School, Fudan University, 12 Central Urumqi Road, Shanghai, China

      Shibao Li, Yuming Chen, Zhihua Kang, Hua Wang, Tingting Hu, Qunfeng Zhang, Yanqun Cai & Ming Guan

    2. Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, China

      Shibao Li

    3. Department of Laboratory Medicine, Huashan Hospital North, Fudan University, Shanghai, China

      Zhiyuan Wu & Ming Guan

    4. Department of Laboratory Medicine, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China

      ** He

    5. Central Laboratory, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China

      **nju Zhang, **ao Xu & Ming Guan

    6. Department of Laboratory Medicine, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, China

      Qunfeng Zhang

    7. Department of Laboratory Medicine, Taizhou Municipal Hospital, Taizhou, Zhejiang, China

      Yanqun Cai

    Authors
    1. Shibao Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Zhiyuan Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Yuming Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Zhihua Kang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Hua Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. ** He
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. **nju Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Tingting Hu
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Qunfeng Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Yanqun Cai
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. **ao Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Ming Guan
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Ming Guan.

    Ethics declarations

    Conflicts of interest

    None

    Additional information

    Shibao Li and Zhiyuan Wu contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    ESM 1

    (DOC 55 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Li, S., Wu, Z., Chen, Y. et al. Diagnostic and prognostic value of tissue and circulating levels of Ephrin-A2 in prostate cancer. Tumor Biol. 37, 5365–5374 (2016). https://doi.org/10.1007/s13277-015-4398-7

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s13277-015-4398-7

    Keywords

    Search

    Navigation