Advertisement

Tumor Biology

, Volume 36, Issue 4, pp 2773–2778 | Cite as

RETRACTED ARTICLE: Bone morphogenetic protein 2 mediates epithelial-mesenchymal transition via AKT and ERK signaling pathways in gastric cancer

  • Anyan Liao
  • Weijie Wang
  • Dawei Sun
  • Yuliang Jiang
  • Suqing Tian
  • Jinna Li
  • Xiangshan Yang
  • Ranran Shi
Research Article

Abstract

Although deregulation of bone morphogenetic protein 2 (BMP2) signaling has been linked to various types of cancers, the relationships between abnormal activation of these signaling pathways and tumorigenesis are not clear in gastric cancer. We hypothesized that BMP2 might be involved in epithelial-mesenchymal transition (EMT) process of gastric cancer. Here, BMPR-II activation and inhibition in gastric cancer cell line AGS were induced with exogenous BMP2 and with BMPR-II small interfering RNA (siRNA), respectively. BMPR-II downstream signal molecules AKT, ERK phosphorylation, and EMT biomarkers (vimentin, snail, N-cadherin, and E-cadherin) were tested using the Western blot. In the present study, our results showed that BMP2 can induce AKT and ERK phosphorylation in a dose-dependent method, and endogenous BMPR-II can be inhibited completely by BMPR-II siRNA in AGS. Notably BMP2 alone treatment can induce the up-regulation of vimentin, snail, and N-cadherin in AGS cells, besides, the down-regulation of E-cadherin also occurred. On the contrary, BMPR-II siRNA significantly prohibited BMP2-induced AKT and ERK phosphorylation, at the same time, EMT biomarkers changes were not observed. On the other hand, BMPR-II knockdown could significantly affect AGS wound closure and the migration ability (p < 0.001) compared to control siRNA and BMP2 alone. In conclusion, this study suggested that EMT process can be triggered by the BMP2/BMPR axis in gastric cancer and then involved in the tumor cell migration, invasion, and metastasis via the activation of PI3K/AKT and MEK/ERK pathways. Our study lays a new foundation for the treatment of gastric cancer through antagonizing BMP2 system.

Keywords

BMP2 EMT AKT ERK Gastric cancer 

Notes

Acknowledgments

We greatly thank other members in Yang & Sandy Lab for the valuable suggestions and writing.

Conflicts of interest

None

References

  1. 1.
    Brenner H, Rothenbacher D, Arndt V. Epidemiology of stomach cancer. Methods Mol Biol. 2009;472:467–77.CrossRefPubMedGoogle Scholar
  2. 2.
    Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet. 2009;374:477–90.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Miao RL, Wu AW. Towards personalized perioperative treatment for advanced gastric cancer. World J Gastroenterol. 2014;20:11586–94.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Koessler T, Roth A, Cacheux W. Early gastric cancer: epidemiology, diagnostic and management. Rev Med Suisse. 2014;10:1118–22.PubMedGoogle Scholar
  5. 5.
    Moustakas A, Heldin P. TGFβ and matrix-regulated epithelial to mesenchymal transition. Biochim Biophys Acta. 1840;2014:2621–34.Google Scholar
  6. 6.
    Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science. 2013;342:1234850.CrossRefPubMedGoogle Scholar
  8. 8.
    Li Y, Ma J, Qian X, Wu Q, Xia J, Miele L, et al. Regulation of EMT by Notch signaling pathway in tumor progression. Curr Cancer Drug Targets. 2013;13:957–62.CrossRefPubMedGoogle Scholar
  9. 9.
    Balogh P, Katz S, Kiss AL. The role of endocytic pathways in TGF-β signaling. Pathol Oncol Res. 2013;19:141–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Gao D, Vahdat LT, Wong S, Chang JC, Mittal V. Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer Res. 2012;72:4883–9.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Derynck R, Zhang Y, Feng XH. Smads: transcriptional activators of TGF-beta responses. Cell. 1998;95:737–40.CrossRefPubMedGoogle Scholar
  12. 12.
    Cao X, Chen D. The BMP signaling and in vivo bone formation. Gene. 2005;357:1–8.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hardwick JC, Van Den Brink GR, Bleuming SA, Ballester I, Van Den Brande JM, Keller JJ, et al. Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon. Gastroenterology. 2004;126:111–21.CrossRefPubMedGoogle Scholar
  14. 14.
    Rosen V. BMP2 signaling in bone development and repair. Cytokine Growth Factor Rev. 2009;20:475–80.CrossRefPubMedGoogle Scholar
  15. 15.
    Bates RC, DeLeo Iii MJ, Mercurio AM. The epithelial–mesenchymal transition of colon carcinoma involves expression of IL-8 and CXCR-1-mediated chemotaxis. Exp Cell Res. 2004;3:315–24.CrossRefGoogle Scholar
  16. 16.
    Wu Y, Ginther C, Kim J, Mosher N, Chung S, Slamon D, et al. Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells. Mol Cancer Res. 2012;3:1597–606.CrossRefGoogle Scholar
  17. 17.
    Rothhammer T, Poser I, Soncin F, Bataille F, Moser M, Bosserhoff AK. Bone morphogenic proteins are overexpressed in malignant melanoma and promote cell invasion and migration. Cancer Res. 2005;65:448–56.PubMedGoogle Scholar
  18. 18.
    Langenfeld EM, Langenfeld J. Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res. 2004;2:141–9.PubMedGoogle Scholar
  19. 19.
    Langenfeld EM, Calvano SE, Abou-Nukta F, Lowry SF, Amenta P, Langenfeld J. The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells. Carcinogenesis. 2003;24:1445–54.CrossRefPubMedGoogle Scholar
  20. 20.
    Langenfeld EM, Kong Y, Langenfeld J. Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5. Oncogene. 2006;25:685–92.CrossRefPubMedGoogle Scholar
  21. 21.
    Langenfeld EM, Bojnowski J, Perone J, Langenfeld J. Expression of bone morphogenetic proteins in human lung carcinomas. Ann Thorac Surg. 2005;80:1028–32.CrossRefPubMedGoogle Scholar
  22. 22.
    Sugimori K, Matsui K, Motomura H, Tokoro T, Wang J, Higa S, et al. BMP-2 prevents apoptosis of the N1511 chondrocytic cell line through PI3K/Akt-mediated NF-kappaB activation. J Bone Min Metab. 2005;23:411–9.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Anyan Liao
    • 1
  • Weijie Wang
    • 2
  • Dawei Sun
    • 3
  • Yuliang Jiang
    • 1
  • Suqing Tian
    • 1
  • Jinna Li
    • 1
  • Xiangshan Yang
    • 4
  • Ranran Shi
    • 5
  1. 1.Department of Radiation OncologyPeking University 3rd HospitalBeijing,China
  2. 2.Department of Emergency SurgeryQilu Hospital of Shandong UniversityJinanChina
  3. 3.Department of Hepatobiliary and Pancreatic SurgeryThe First Hospital of Jilin UniversityChangchunChina
  4. 4.Department of PathologyAffiliated Hospital of Shandong Academy of Medical SciencesJinanChina
  5. 5.Department of General SurgeryShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina

Personalised recommendations