Skip to main content

Advertisement

Log in

Endothelial cell protein C receptor promotes MGC803 gastric cancer cells proliferation and migration by activating ERK1/2

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

The endothelial cell protein C receptor (EPCR) has been reported to be involved in the development of several human cancers. However, the role of EPCR in gastric cancer progression has not been clarified. In this study, we show for the first time that EPCR is related to gastric cancer. Our results indicate that EPCR is highly expressed in clinical gastric cancer tissue. Knockdown of EPCR by small interference RNA suppressed the proliferation and migration of MGC803 gastric cancer cells dominantly. Blocking antibodies to protease-activated receptor-1(PAR1) also suppressed the proliferation and migration of MGC803 cells. Knockdown EPCR and blocking PAR1 inhibit activation of extracellular signaling-regulated kinases 1 and 2 (ERK1/2). Taken together, these results indicate that EPCR contributes to the proliferation and migration of MGC803 gastric cancer cells by activating ERK1/2, and this effect of EPCR may be dependent on PAR1. Therefore, EPCR may be act as a novel therapeutic target for inhibiting cell growth in gastric cancer.

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

Access this article

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. Globocan 2012. http://globocan.iarc.fr/. Accessed 31 March 2014.

  2. Fock KM. Review article: the epidemiology and prevention of gastric cancer. Aliment Pharmacol Ther. 2014;40(3):250–60.

    Article  CAS  PubMed  Google Scholar 

  3. McLean MH, El-Omar EM. Genetics of gastric cancer. Nat Rev Gastroenterol Hepatol. 2014;11(11):664–74.

    Article  CAS  PubMed  Google Scholar 

  4. Zhaode Bu, Ji Jiafu. A current view of gastric cancer in China. Transl Gastrointest Cancer. 2013;2(S1):1–4.

    Google Scholar 

  5. Fukudome K, Esmon CT. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem. 1994;269(42):26486–91.

    CAS  PubMed  Google Scholar 

  6. Haller H, Ziegler W, Lindschau C, et al. Endothelial cell tyrosine kinase receptor and G protein-coupled receptor activation involves distinct protein kinase C isoforms. Arterioscler Thromb Vasc Biol. 1996;16(5):678–86.

    Article  CAS  PubMed  Google Scholar 

  7. Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood. 2007;109(8):3161–72.

    Article  CAS  PubMed  Google Scholar 

  8. Mohan Rao LV, Esmon CT, Pendurthi UR. Endothelial cell protein C receptor: a multiliganded and multifunctional receptor. Blood. 2014;124(10):1553–62.

    Article  PubMed  Google Scholar 

  9. Bouwens EA, Stavenuiter F, Mosnier LO. Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway. J Thromb Haemost. 2013;11(Suppl 1):242–53.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Sen P, Gopalakrishnan R, Kothari H, et al. Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signaling and barrier protection. Blood. 2011;117(11):3199–208.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Thiyagarajan M, Cheng T, Zlokovic BV. Endothelial cell protein C receptor: role beyond endothelium? Circ Res. 2007;100(2):155–7.

    Article  CAS  PubMed  Google Scholar 

  12. Tsuneyoshi N, Fukudome K, Horiguchi S, et al. Expression and anticoagulant function of the endothelial cell protein C receptor (EPCR) in cancer cell lines. Thromb Haemost. 2001;85(2):356–61.

    CAS  PubMed  Google Scholar 

  13. Scheffer GL, Flens MJ, Hageman S, et al. Expression of the vascular endothelial cell protein C receptor in epithelial tumour cells. Eur J Cancer. 2002;38(11):1535–42.

    Article  CAS  PubMed  Google Scholar 

  14. Anton I, Molina E, Luis-Ravelo D, et al. Receptor of activated protein C promotes metastasis and correlates with clinical outcome in lung adenocarcinoma. Am J Respir Crit Care Med. 2012;186(1):96–105.

    Article  CAS  PubMed  Google Scholar 

  15. Heng W, Mu CY, Chen C, et al. Endothelial cell protein C receptor (EPCR) is expressed by lung carcinoma and correlated with clinical parameters. Clin Lab. 2013;59(3–4):375–80.

    CAS  PubMed  Google Scholar 

  16. Ducros E, Mirshahi S, Azzazene D, et al. Endothelial protein C receptor expressed by ovarian cancer cells as a possible biomarker of cancer onset. Int J Oncol. 2012;41(2):433–40.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Beaulieu LM, Church FC. Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1. Exp Cell Res. 2007;313(4):677–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Bretschneider E, Uzonyi B, Weber AA, et al. Human vascular smooth muscle cells express functionally active endothelial cell protein C receptor. Circ Res. 2007;100(2):255–62.

    Article  CAS  PubMed  Google Scholar 

  19. Domotor E, Benzakour O, Griffin JH, et al. Activated protein C alters cytosolic calcium flux in human brain endothelium via binding to endothelial protein C receptor and activation of protease activated receptor-1. Blood. 2003;101(12):4797–801.

    Article  PubMed  Google Scholar 

  20. Gramling MW, Beaulieu LM, Church FC. Activated protein C enhances cell motility of endothelial cells and MDA-MB-231 breast cancer cells by intracellular signal transduction. Exp Cell Res. 2010;316(3):314–28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Schaffner F, Yokota N, Carneiro-Lobo T, et al. Endothelial protein C receptor function in murine and human breast cancer development. PLoS One. 2013;8(4):e61071.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Keshava S, Kothari H, Rao LV, Pendurthi UR. Influence of endothelial cell protein C receptor on breast cancer development. J Thromb Haemost. 2013;11(11):2062–5.

    Article  CAS  PubMed  Google Scholar 

  23. Keshava S, Sahoo S, Tucker TA, Idell S, Rao LV, Pendurthi UR. Endothelial cell protein C receptor opposes mesothelioma growth driven by tissue factor. Cancer Res. 2013;73(13):3963–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Van Sluis GL, Niers TM, Esmon CT, et al. Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated vascular endothelial barrier enhancement. Blood. 2009;114(9):1968–73.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Bezuhly M, Cullen R, Esmon CT, et al. Role of activated protein C and its receptor in inhibition of tumor metastasis. Blood. 2009;113(14):3371–4.

    Article  CAS  PubMed  Google Scholar 

  26. Van Sluis GL, Brüggemann LW, Esmon CT, et al. Endogenous activated protein C is essential for immune-mediated cancer cell elimination from the circulation. Cancer Lett. 2011;306(1):106–10.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81101493).

Conflict of interest

The authors state that they have no conflict of interest.

Ethical standard

These specimens were collected from the patients registered at the above-mentioned hospital, and written informed consent was obtained from the patients. This study was approved by the ethics committee of the hospital.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peng Zhang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Q., Liu, Q., Wang, T. et al. Endothelial cell protein C receptor promotes MGC803 gastric cancer cells proliferation and migration by activating ERK1/2. Med Oncol 32, 162 (2015). https://doi.org/10.1007/s12032-015-0614-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-015-0614-y

Keywords

Navigation