Skip to main content

Advertisement

SpringerLink
Log in

Down-regulation of EphB4 phosphorylation is necessary for esophageal squamous cell carcinoma tumorigenecity

  • Research Article
  • Published:
Tumor Biology

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Eph/ephrin signaling system plays a very important role in the tumorigenesis and the formation of blood vessel. However, the function of EphB4 and its ligand ephrin B2 in the carcinogenesis of esophageal squamous cell carcinoma (ESCC) is not fully understood. Here, it was found that the expression of EphB4 was up-regulated in ESCC tissues compared with the paired normal tissues, while ephrin B2 was down-regulated in ESCC samples. Phosphorylation of EphB4 induced by its ligand ephrin B2-Fc inhibited the growth, migration and colony formation of ESCC cells. Moreover, over-expression of EphB4 or EphB4 kinase dead mutant (EphB4 KD) in ESCC cells promoted cell growth and migration, suggesting EphB4 promoted cell growth and migration independent of its kinase activity. Furthermore, we found that EphB4 interacted with the adaptor protein RACK1 and RACK1 decreased the phosphorylation level of EphB4. Taken together, our study revealed the important function and regulation of EphB4 in the progression of ESCC and suggested EphB4 as a novel target for the treatment of ESCC.

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. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J Clin. 2012;60:277–300.

    Article  Google Scholar 

  2. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349:2241–52.

    Article  CAS  PubMed  Google Scholar 

  3. Tachibana M, Kinugasa S, Yoshimura, et al. Extended esophagectomy with 3-field lymph node dissection for esophageal cancer. Arch Surg. 2003;138:1383–9.

    Article  PubMed  Google Scholar 

  4. Kopreski MS, Witters L, Brennan WAJ, et al. Protein tyrosine kinase activity in breast cancer and its relation to prognostic indicators. Anticancer Res. 1996;16:3037–41.

    CAS  PubMed  Google Scholar 

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

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Surawska H, Ma PC, Salgia R. The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev. 2004;15:419–33.

    Article  CAS  PubMed  Google Scholar 

  7. Kim YH, Hu H, Guevara GS, et al. Artery and vein size is balanced by Notch and ephrin B2/B4 during angiogenesis. Development. 2008;135:3755–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Bruhl T, Urbich C, Aicher D, et al. Homeobox A9 transcriptionally regulates the EphB4 receptor to modulate endothelial cell migration and tube formation. Circ Res. 2004;94:743–51.

    Article  CAS  PubMed  Google Scholar 

  9. Steinle JJ, Meininger CJ, Forough R, et al. EphB4 receptor signaling mediates endothelial cell migration and proliferation via PI3K pathway. J Biol Chem. 2002;277:43830–5.

    Article  CAS  PubMed  Google Scholar 

  10. Hasina R, Mollberg N, Kawada I. Critical role for the receptor tyrosine kinase EPHB4 in esophageal cancers. Cancer Res. 2013;73:184–94.

    Article  CAS  PubMed  Google Scholar 

  11. Hu HQ, Tao Z, Wang MS, et al. RACK1 promoted the growth and migration of the cancer cells in the progression of esophageal squamous cell carcinoma. Tumor Biol. 2013;34:3893–9.

    Article  CAS  Google Scholar 

  12. Xia G, Kumar SR, Masood R, et al. EphB4 expression and biological significance in prostate cancer. Cancer Res. 2005;65:4623–32.

    Article  CAS  PubMed  Google Scholar 

  13. Xia G, Kumar SR, Stein JP, 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 

  14. Kumar SR, Masood R, Spannuth WA, et al. The receptor tyrosine kinase Ephb4 is overexpressed in ovarian cancer, provides signals and predicts poor outcome. Br J Cancer. 2007;96:1083–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Noren NK, Foos G, Hauser CA, et al. The EphB4 receptor suppresses breast cancer cell tumorigenecity through an Abl–Crk pathway. Nat Cell Biol. 2006;8:815–25.

    Article  CAS  PubMed  Google Scholar 

  16. Deng YZ, Yao F, Li JJ, et al. RACK1 Suppresses gastric tumorigenesis by stabilizing beta-catenin destruction complex. Gastroenterology. 2012;142:812–23.

    Article  CAS  PubMed  Google Scholar 

  17. Li G, Ji XD, Gao H, et al. EphB3 mediates kinase-dependent suppression of non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signaling complex. Nat Commun. 2012;3:667. doi:10.1038/ncomms1675.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiovascular Surgery, First Affiliated Hospital of Soochow University, 188 Shizijie, Suzhou, 215000, China

    Fengqing Hu, Zhenya Shen, Xiaolin Wang & Fei Hua

  2. Department of Cardiothoracic Surgery, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, China

    Fengqing Hu

  3. Department of Neurology, General Hospital of Jinan Military Command, Jinan, Shandong, 250031, China

    Zhen Tao

Authors
  1. Fengqing Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhen Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhenya Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaolin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fei Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhenya Shen.

Additional information

F. Hu and Z. Tao contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, F., Tao, Z., Shen, Z. et al. Down-regulation of EphB4 phosphorylation is necessary for esophageal squamous cell carcinoma tumorigenecity. Tumor Biol. 35, 7225–7232 (2014). https://doi.org/10.1007/s13277-014-1955-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-1955-4

Keywords

Search

Navigation