Skip to main content

Advertisement

SpringerLink
Log in

C23 protein meditates bone morphogenetic protein-2-mediated EMT via up-regulation of Erk1/2 and Akt in gastric cancer

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

Abstract

In our previous study, the epithelial-to-mesenchymal transition (EMT) has been identified to be involved in gastric cancer progression. Notably, nuclear protein C23 and bone morphogenetic protein-2 (BMP2) have been linked into EMT. However, the specific mechanisms underlying BMP2 pathway-mediated EMT are not still unraveled. In this study, we adopted immunohistochemistry and immunoblotting to determine the expression of C23 and BMP2 receptor II (BMPR-II) in 90 gastric cancer samples and cell lines. Subsequently, relevant cell lines were selected to be treated with si-C23 or si-BMPRII and the detection of in vitro assay. Our results revealed that both C23 and BMPRII were aberrantly and constitutively expressed in gastric cancer specimens and cell lines, whose expression was positively associated with metastasis, stage and differentiation, and portended poor survival outcome of gastric cancer patients. In vitro assay validated the increased expression of p-Erk1/2, p-Akt, vimentin, N-cadherin, and MMP2 in BMP2-stimulated MGC803 cells, which was in a dose-dependent manner. By contrast, si-C23 treatment attenuated the BMP2-stimulated expression of p-Erk1/2, p-Akt, vimentin, N-cadherin, and MMP2. Also, the treatment of either si-C23 or si-BMPRII decreased the ability of migration and invasion of MGC803 cells. In conclusion, C23 mediates BMP2-induced EMT progression via the up-regulation of Erk1/2 and Akt signaling pathway in gastric cancer, which indicated both C23 and BMPRII pathway could be recommended as prospective targets or biomarkers to antagonize the progression of gastric cancer.

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. Assaraf YG, Leamon CP, Reddy JA. The folate receptor as a rational therapeutic target for personalized cancer treatment. Drug Resist Updat. 2014;17:89–95.

    Article  PubMed  Google Scholar 

  2. Lianos GD, Rausei S, Ruspi L, Galli F, Mangano A, Roukos DH, et al. Laparoscopic gastrectomy for gastric cancer: current evidences. Int J Surg. 2014;12:1369–73.

    Article  PubMed  Google Scholar 

  3. Deng JY, Liang H. Clinical significance of lymph node metastasis in gastric cancer. World J Gastroenterol. 2014;20:3967–75.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Velho S, Fernandes MS, Leite M, Figueiredo C, Seruca R. Causes and consequences of microsatellite instability in gastric carcinogenesis. World J Gastroenterol. 2014;20:16433–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. McCormack N, O’Dea S. Regulation of epithelial to mesenchymal transition by bone morphogenetic proteins. Cell Signal. 2013;25(12):2856–62.

    Article  CAS  PubMed  Google Scholar 

  6. Derynck R, Zhang Y, Feng XH. Smads: transcriptional activators of TGF-beta responses. Cell. 1998;95:737–40.

    Article  CAS  PubMed  Google Scholar 

  7. Cao X, Chen D. The BMP signaling and in vivo bone formation. Gene. 2005;357:1–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. González V, Guo K, Hurley L, et al. Identification and characterization of nucleolin as a c-myc G-quadruplex-binding protein. J Biol Chem. 2009;284:23622–35.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Wu DM, Zhang P, Liu RY, et al. Phosphorylation and changes in the distribution of nucleolin promote tumor metastasis via the PI3K/Akt pathway in colorectal carcinoma. FEBS Lett. 2014;588:1921–9.

    Article  CAS  PubMed  Google Scholar 

  10. Galzio R, Rosati F, Benedetti E, et al. Glycosilated nucleolin as marker for human gliomas. J Cell Biochem. 2012;113:571–9.

    Article  CAS  PubMed  Google Scholar 

  11. Hovanessian AG. Midkine, a cytokine that inhibits HIV infection by binding to the cell surface expressed nucleolin. Cell Res. 2006;16:174–81.

    Article  CAS  PubMed  Google Scholar 

  12. Li W, Dunmore BJ, Morrell NW. Bone morphogenetic protein type II receptor mutations causing protein misfolding in heritable pulmonary arterial hypertension. Proc Am Thorac Soc. 2010;7:395–8.

    Article  CAS  PubMed  Google Scholar 

  13. Upton PD, Morrell NW. TGF-beta and BMPR-II pharmacology: implications for pulmonary vascular diseases. Curr Opin Pharmacol. 2009;9:274–80.

    Article  CAS  PubMed  Google Scholar 

  14. Hung CY, Yang WB, Wang SA, et al. Nucleolin enhances internal ribosomal entry site (IRES)-mediated translation of Sp1 in tumorigenesis. Biochim Biophys Acta. 2014;1843:2843–54.

    Article  CAS  PubMed  Google Scholar 

  15. Shen N, Yan F, Pang J, et al. A nucleolin-DNMT1 regulatory axis in acute myeloid leukemogenesis. Oncotarget. 2014;5:5494–509.

    PubMed Central  PubMed  Google Scholar 

  16. Zeng W, Chang H, Ma M, Li Y. CCL20/CCR6 promotes the invasion and migration of thyroid cancer cells via NF-kappa B signaling-induced MMP-3 production. Exp Mol Pathol. 2014;97:184–90.

    Article  CAS  PubMed  Google Scholar 

  17. Du D, Liu Y, Qian H, Zhang B, Tang X, Zhang T, et al. The effects of the CCR6/CCL20 biological axis on the invasion and metastasis of hepatocellular carcinoma. Int J Mol Sci. 2014;15:6441–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Shi Y, Wu H, Zhang M, Ding L, Meng F, Fan X. Expression of the epithelial-mesenchymal transition-related proteins and their clinical significance in lung adenocarcinoma. Diagn Pathol. 2013;8:89.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Shih JY, Yang PC. The EMT regulator slug and lung carcinogenesis. Carcinogenesis. 2011;32:1299–304.

    Article  CAS  PubMed  Google Scholar 

  20. Chowdhury I, Thompson WE, Thomas K. Prohibitins role in cellular survival through Ras-Raf-MEK-ERK pathway. J Cell Physiol. 2014;229:998–1004.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Neuzillet C, Tijeras-Raballand A, de Mestier L, Cros J, Faivre S, Raymond E. MEK in cancer and cancer therapy. Pharmacol Ther. 2014;141:160–71.

    Article  CAS  PubMed  Google Scholar 

  22. Yang P, Wang G, Huo H, Li Q, Zhao Y, Liu Y. SDF-1/CXCR4 signaling up-regulates survivin to regulate human sacral chondrosarcoma cell cycle and epithelial-mesenchymal transition via ERK and PI3K/AKT pathway. Med Oncol. 2015;32:377.

    Article  PubMed  Google Scholar 

  23. Zhou SL, Zhou ZJ, Hu ZQ, Li X, Huang XW, Wang Z, et al. CXCR2/CXCL5 axis contributes to epithelial-mesenchymal transition of HCC cells through activating PI3K/Akt/GSK-3β/Snail signaling. Cancer Lett. 2015;358:124–35.

    Article  CAS  PubMed  Google Scholar 

  24. Bhat FA, Sharmila G, Balakrishnan S, Arunkumar R, Elumalai P, Suganya S, et al. Quercetin reverses EGF-induced epithelial to mesenchymal transition and invasiveness in prostate cancer (PC-3) cell line via EGFR/PI3K/Akt pathway. J Nutr Biochem. 2014;25:1132–9.

    Article  CAS  PubMed  Google Scholar 

  25. Wu CD, Chou HW, Kuo YS, et al. Nucleolin antisense oligodeoxynucleotides induce apoptosis and may be used as a potential drug for nasopharyngeal carcinoma therapy. Oncol Rep. 2012;27:94–100.

    CAS  PubMed  Google Scholar 

  26. Hu J, Lin M, Liu T, et al. DIGE-based proteomic analysis identifies nucleophosmin/B23 and nucleolin C23 as over-expressed proteins in relapsed/refractory acute leukemia. Leuk Res. 2011;35:1087–92.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We greatly thank other members of our lab for valuable suggestions and writing.

Conflict of interest

None.

Author information

Author notes

    Authors and Affiliations

    1. The Third Department of Geriatrics, The First Hospital of Shijiazhuang City, 36# Fanxi Road, Shijiazhuang, 050011, Hebei, People’s Republic of China

      Yonggang Yang & Jianping Zhang

    2. Department of Ultrasonography, The First Hospital of Shijiazhuang City, Shijiazhuang, 050011, People’s Republic of China

      Chunyan Yang

    Authors
    1. Yonggang Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Chunyan Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jianping Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Jianping Zhang.

    Additional information

    Yonggang Yang and Chunyan Yang have contributed equally to this work as the co-first author.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Yang, Y., Yang, C. & Zhang, J. C23 protein meditates bone morphogenetic protein-2-mediated EMT via up-regulation of Erk1/2 and Akt in gastric cancer. Med Oncol 32, 76 (2015). https://doi.org/10.1007/s12032-015-0547-5

    Download citation

    • Received:

    • Accepted:

    • Published:

    • DOI: https://doi.org/10.1007/s12032-015-0547-5

    Keywords

    Search

    Navigation