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Tumor Biology

, Volume 36, Issue 5, pp 3621–3628 | Cite as

Involvement of NEDD9 in the invasion and migration of gastric cancer

  • Jin Feng
  • Jinpeng Zhao
  • Haibin Xie
  • Yong Yin
  • Guanghua Luo
  • Jun Zhang
  • Yuehua Feng
  • Zhong Li
Research Article

Abstract

Recent studies have demonstrated that neural precursor cell expressed, developmentally downregulated 9 (NEDD9) is highly expressed in various tumor tissues and cell lines. However, research on the role of NEDD9 in gastric cancer (GC) is rare, and the potential mechanism in tumor progression has not yet been explored. In this study, we investigated the role and mechanism of NEDD9 in GC. The expression of NEDD9 in GC tissues and cell lines was measured by immunohistochemistry, qRT-PCR, and Western blot, respectively. Inhibiting NEDD9 expression was carried out by siRNA transfection, and upregulating of NEDD9 was via NEDD9 overexpression plasmid. The ability of proliferation, migration, and invasion was detected by MTT assay, scratch wound assay, and transwell assay, respectively. The expression of vimentin, E-cadherin, Zeb1, and Zeb2 was measured by Western blot and qRT-PCR. We found that NEDD9 expression was dramatically increased both in GC tissues and cell lines, and the expression was significantly related to GC development. Knockdown of NEDD9 in SGC-7901 strongly inhibited its malignant capacity in vitro. Meanwhile, upregulation of NEDD9 in GES-1 increased the malignant capacity. In addition, the expression of vimentin, Zeb1, and Zeb2 was positively correlated with NEDD9, while E-cadherin was opposite. Collectively, our findings suggest that NEDD9 acts as an oncogene and promotes GC metastasis via EMT.

Keywords

NEDD9 GC Migration Invasion EMT 

Notes

Acknowledgments

This work was supported by the major project of Changzhou Health bureau [NO. ZD200906], the applied basic research project of Changzhou science and technology bureau [NO. CJ20140047].

Conflict of interest

None.

References

  1. 1.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al.: GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet], 2013.Google Scholar
  2. 2.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71–96.CrossRefPubMedGoogle Scholar
  3. 3.
    Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet. 2009;374:477–90.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Law SF, Estojak J, Wang B, Mysliwiec T, Kruh G, Golemis EA. Human enhancer of filamentation 1, a novel p130cas-like docking protein, associates with focal adhesion kinase and induces pseudohyphal growth in Saccharomyces cerevisiae. Mol Cell Biol. 1996;16:3327–37.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Minegishi M, Tachibana K, Sato T, Iwata S, Nojima Y, Morimoto C. Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta 1 integrinmediated signaling in lymphocytes. J Exp Med. 1996;184:1365–75.CrossRefPubMedGoogle Scholar
  6. 6.
    Natarajan M, Stewart JE, Golemis EA, Pugacheva EN, Alexandropoulos K, Cox BD, et al. HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells. Oncogene. 2006;25(12):1721–32.CrossRefPubMedGoogle Scholar
  7. 7.
    Kim M, Gans JD, Nogueira C, Wang A, Paik JH, Feng B, et al. Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell. 2006;125(7):1269–81.CrossRefPubMedGoogle Scholar
  8. 8.
    Kong C, Wang C, Wang L, Ma M, Niu C, Sun X, et al. NEDD9 is a positive regulator of epithelial-mesenchymal transition and promotes invasion in aggressive breast cancer. PLoS One. 2011;6(7):e22666.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Li Y, Bavarva JH, Wang Z, Guo J, Qian C, Thibodeau SN, et al. HEF1, a novel target of Wnt signaling, promotes colonic cell migration and cancer progression. Oncogene. 2011;30(23):2633–43.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Kumar S, Tomooka Y, Noda M. Identification of a set of genes with developmentally down-regulated expression in the mouse brain. Biochem Biophys Res Commun. 1992;185:1155–61.CrossRefPubMedGoogle Scholar
  11. 11.
    O’Neill GM, Seo S, Serebriiskii IG, Lessin SR, Golemis EA. A new central scaffold for metastasis: parsing HEF1/Cas-L/NEDD9. Cancer Res. 2007;67(19):8975–9.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Tikhmyanova N, Little JL, Golemis EA. CAS proteins in normal and pathological cell growth control. Cell Mol Life Sci. 2010;67(7):1025–48.CrossRefPubMedGoogle Scholar
  13. 13.
    Singh M, Cowell L, Seo S, O’Neill G, Golemis E. Molecular basis for HEF1/NEDD9/Cas-L action as a multifunctional co-ordinator of invasion, apoptosis and cell cycle. Cell Biochem Biophys. 2007;48(1):54–72.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Feng Y, Wang Y, Wang Z, Fang Z, Li F, Gao Y, et al. The CRTC1-NEDD9 signaling axis mediates lung cancer progression caused by LKB1 loss. Cancer Res. 2012;72:6502–11.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhang Q, Wang H, Ma Y, Zhang J, He X, Ma J, et al. Overexpression of Nedd9 is a prognostic marker of human gastric cancer. Med Oncol. 2014;31(7):33.CrossRefPubMedGoogle Scholar
  16. 16.
    Liu Y, Wang D, Zhao KL, Zhu JW, Yin HB, Wei YZ, et al. NEDD9 overexpression correlates with poor prognosis in gastric cancer. Tumour Biol. 2014;35(7):6351–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Shi R, Wang L, Wang T, Xu J, Wang F, Xu M. NEDD9 overexpression correlates with the progression and prognosis in gastric carcinoma. Med Oncol. 2014;31(3):852.CrossRefPubMedGoogle Scholar
  18. 18.
    Zeng G, Gao L, Yu RK. Reduced cell migration, tumor growth and experimental metastasis of rat F-11 cells whose expression of GD3-synthase is suppressed. Int J Cancer. 2000;88(1):53–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Shin KD, Lee MY, Shin DS, Lee S, Son KH, Koh S, et al. Blocking tumor cell migration and invasion with biphenyl isoxazole derivative KRIBB3, a synthetic molecule that inhibits Hsp27 phosphorylation. J Biol Chem. 2005;280(50):41439–48.CrossRefPubMedGoogle Scholar
  20. 20.
    Mitra SK, Schlaepfer DD. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006;18:516–23.CrossRefPubMedGoogle Scholar
  21. 21.
    Kiyokawa E, Hashimoto Y, Kurata T, Sugimura H, Matsuda M. Evidence that DOCK180 up-regulates signals from the CrkII-p130(Cas) complex. J Biol Chem. 1998;273:24479–84.CrossRefPubMedGoogle Scholar
  22. 22.
    Klemke RL, Leng J, Molander R, Brooks PC, Vuori K, Cheresh DA. CAS/Crk coupling serves as a “molecular switch” for induction of cell migration. J Cell Biol. 1998;140:961–72.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sadok A, Marshall C: Rho-GTPases: Masters of cell migration. Small GTPases 5. pii: e29710, 2014.Google Scholar
  24. 24.
    Natarajan M, Stewart J, Golemis EA, Pugacheva EN, Alexandropoulos K, Cox BD. HEF1 is a necessary and specific downstream effcctor of FAK that promotes the migration of glioblastoma cells. Oncogene. 2006;25:1721–32.CrossRefPubMedGoogle Scholar
  25. 25.
    Leshem O, Madar S, Kogan-Sakin I, Kamer I, Goldstein I, Brosh R, et al. TMPRSS2/ERG promotes epithelial to mesenchymal transition through the ZEB1/ZEB2 axis in a prostate cancer model. PLoS One. 2011;6(7):e21650.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Jin Y, Li F, Zheng C, Wang Y, Fang Z, Guo C, et al. NEDD9 promotes lung cancer metastasis through epithelial-mesenchymal transition. Int J Cancer. 2014;134(10):2294–304.CrossRefPubMedGoogle Scholar
  27. 27.
    Prudkin L, Liu DD, Ozburn NC, Sun M, Behrens C, Tang X, et al. Epithelial-tomesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung. Mod Pathol. 2009;22(5):668–78.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelialmesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.CrossRefPubMedGoogle Scholar
  29. 29.
    Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14:818–29.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Jin Feng
    • 1
  • Jinpeng Zhao
    • 1
  • Haibin Xie
    • 1
  • Yong Yin
    • 1
  • Guanghua Luo
    • 2
  • Jun Zhang
    • 2
  • Yuehua Feng
    • 2
  • Zhong Li
    • 1
  1. 1.Department of General SurgeryThe First People’s Hospital of Changzhou, the Third Affiliated Hospital of Soochow UniversityChangzhouChina
  2. 2.Department of Comprehensive laboratoryThe First People’s Hospital of Changzhou, the Third Affiliated Hospital of Soochow UniversityChangzhouChina

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