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Smad4 mediates malignant behaviors of human ovarian carcinoma cell through the effect on expressions of E-cadherin, plasminogen activator inhibitor-1 and VEGF

  • Chen, Chen (Key Laboratory for Proteomics of Liaoning Province, Dalian Medical University) ;
  • Sun, Ming-Zhong (Key Laboratory for Proteomics of Liaoning Province, Dalian Medical University) ;
  • Liu, Shuqing (Key Laboratory for Proteomics of Liaoning Province, Dalian Medical University) ;
  • Yeh, Dongmei (Key Laboratory for Proteomics of Liaoning Province, Dalian Medical University) ;
  • Yu, Lijun (Key Laboratory for Proteomics of Liaoning Province, Dalian Medical University) ;
  • Song, Yang (Key Laboratory for Proteomics of Liaoning Province, Dalian Medical University) ;
  • Gong, Linlin (Key Laboratory for Proteomics of Liaoning Province, Dalian Medical University) ;
  • Hao, Lihong (Key Laboratory for Proteomics of Liaoning Province, Dalian Medical University) ;
  • Hu, Jun (Key Laboratory for Proteomics of Liaoning Province, Dalian Medical University) ;
  • Shao, Shujuan (Key Laboratory for Proteomics of Liaoning Province, Dalian Medical University)
  • Received : 2010.04.08
  • Accepted : 2010.07.20
  • Published : 2010.08.31

Abstract

Smad4 is involved in cancer progression and metastasis. Using a pair of human syngeneic epithelial ovarian cancer cells with low (HO-8910) and high (HO-8910PM) metastatic abilities, we aimed to reveal the role of Smad4 in ovarian cancer metastasis in vitro. Smad4 was down-regulated in HO-8910PM cell line relative to HO-8910 by implicating Smad4 was probably a potential tumor suppressor gene for ovarian cancer. Re-expression of Smad4 decreased the migration ability and inhibited the invasion capacity of HO-8910PM, while promoted the cell adhesion capacity for HO-8910PM. The stable expression of Smad4 increased the expression of E-cadherin, reduced the expression of plasminogen activator inhibitor-1 (PAI-1) and slightly down-regulated the expression of VEGF. Smad4 suppresses human ovarian cancer cell metastasis potential through its effect on the expressions of PAI-1, E-cadherin and VEGF. Results from current work implicate Smad4 might suppress the invasion and metastasis of human ovarian tumor cells through a TGF-$\beta$/Smad-mediated pathway.

Keywords

References

  1. Ouyang, G., Yao, L., Ruan, K., Song, G., Mao, Y. and Bao, S. (2009) Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways. Cell Biol. Int. 33, 1237-1244. https://doi.org/10.1016/j.cellbi.2009.08.011
  2. Zhang, Y., Ba, Y., Liu, C., Sun, G., Ding, L., Gao, S., Hao, J., Yu, Z., Zhang, J. and Zen, K. (2007) PGC-1alpha induces apoptosis in human epithelial ovarian cancer cells through a PPARgamma-dependent pathway. Cell Res. 17, 363-373. https://doi.org/10.1038/cr.2007.11
  3. Jemal, A., Thomas, A., Murray, T. and Thun, M. (2002) Cancer statistics, 2002. CA. Cancer J. Clin. 52, 23-47. https://doi.org/10.3322/canjclin.52.1.23
  4. Zhang, L., Conejo-Garcia, J. R., Katsaros, D., Gimotty, P. A., Massobrio, M., Regnani, G., Makrigiannakis, A., Gray, H., Schlienger, K. and Liebman, M. N. (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203-213. https://doi.org/10.1056/NEJMoa020177
  5. Wooster, R. and Weber, B. L. (2003) Breast and ovarian cancer. N. Engl. J. Med. 348, 2339-2347. https://doi.org/10.1056/NEJMra012284
  6. Hahn, S. A., Schutte, M., Hoque, A. T., Moskaluk, C. A., da Costa, L. T., Rozenblum, E., Weinstein, C. L., Fischer, A., Yeo, C. J., Hruban, R. H. and Kern, S. E. (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350-353. https://doi.org/10.1126/science.271.5247.350
  7. Inman, G. J., Nicolas, F. J. and Hill, C. S. (2002) Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Mol. Cell 10, 283-294. https://doi.org/10.1016/S1097-2765(02)00585-3
  8. Moustakas, A., Souchelnytskyi, S. and Heldin, C. H. (2001) Smad regulation in TGF-beta signal transduction. J. Cell Sci. 114, 4359-4369.
  9. Muller, N., Reinacher-Schick, A., Baldus, S., van Hengel, J., Berx, G., Baar, A., van Roy, F., Schmiegel, W. and Schwarte-Waldhoff, I. (2002) Smad4 induces the tumor suppressor E-cadherin and P-cadherin in colon carcinoma cells. Oncogene 21, 6049- 6058. https://doi.org/10.1038/sj.onc.1205766
  10. Losi, L., Bouzourene, H. and Benhattar, J. (2007) Loss of Smad4 expression predicts liver metastasis in human colorectal cancer. Oncol. Rep. 17, 1095-1099.
  11. Zhao, S., Venkatasubbarao, K., Lazor, J. W., Sperry, J., Jin, C., Cao, L. and Freeman, J. W. (2008) Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Res. 68, 4221-4228. https://doi.org/10.1158/0008-5472.CAN-07-5123
  12. Ke, Z., Zhang, X., Ma, L. and Wang, L. (2008) Expression of DPC4/Smad4 in non-small-cell lung carcinoma and its relationship with angiogenesis. Neoplasia 55, 323-329.
  13. Sunde, J. S., Donninger, H., Wu, K., Johnson, M. E., Pestell, R. G., Rose, G. S., Mok, S. C., Brady, J., Bonome, T. and Birrer, M. J. (2006) Expression profiling identifies altered expression of genes that contribute to the inhibition of transforming growth factor-beta signaling in ovarian cancer. Cancer Res. 66, 8404-8412. https://doi.org/10.1158/0008-5472.CAN-06-0683
  14. Shenhua, X., Lijuan, Q., Hanzhou, N., Xinghao, N., Chihong, Z., Gu, Z., Weifang, D. and Yongliang, G. (1999) Establishment of a highly metastatic human ovarian cancer cell line (HO-8910PM) and its characterization. J. Exp. Clin. Cancer Res. 18, 233-239.
  15. Shi, J., Wan, Y. and Di, W. (2008) Effect of hypoxia and re-oxygenation on cell invasion and adhesion in human ovarian carcinoma cells. Oncol. Rep. 20, 803-807.
  16. Chen, H., Yang, W. W., Wen, Q. T., Xu, L. and Chen, M. (2009) TGF-beta induced fibroblast activation protein expression, fibroblast activation protein expression increases the proliferation, adhesion, and migration of HO-8910PM. Exp. Mol. Pathol. 87, 187-194.
  17. Dai, L., Gu, L., Ding, C., Qiu, L. and Di, W. (2009) TWEAK promotes ovarian cancer cell metastasis via NF-kappaB pathway activation and VEGF expression. Cancer Lett. 283, 159-167. https://doi.org/10.1016/j.canlet.2009.03.036
  18. Ma, W., Yu, H., Wang, Q., Bao, J., Yan, J. and Jin, H. (2004) In vitro biological activities of transmembrane superantigen staphylococcal enterotoxin A fusion protein. Cancer Immunol. Immunother. 53, 118-124. https://doi.org/10.1007/s00262-003-0437-0
  19. Sun, H., Sun, C. and Pan, Y. (2005) Cytotoxic activity and constituents of the volatile oil from the roots of Patrinia scabra Bunge. Chem. Biodivers. 2, 1351-1357. https://doi.org/10.1002/cbdv.200590107
  20. Zhang, Y. B., Peng, X. Y. and Sun, H. X. (2008) A new cytotoxic, apoptosis-inducing triterpenoid from the rhizomes of Astilbe chinensis. Chem. Biodivers. 5, 189-196. https://doi.org/10.1002/cbdv.200890010
  21. Sahai, E. (2005) Mechanisms of cancer cell invasion. Curr. Opin. Genet. Dev. 15, 87-96. https://doi.org/10.1016/j.gde.2004.12.002
  22. Kemler, R. (1993) From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet. 9, 317-321. https://doi.org/10.1016/0168-9525(93)90250-L
  23. Shapiro, L., Fannon, A. M., Kwong, P. D., Thompson, A., Lehmann, M. S., Grubel, G., Legrand, J. F., Als-Nielsen, J., Colman, D. R. and Hendrickson, W. A. (1995) Structural basis of cell-cell adhesion by cadherins. Nature 374, 327-337. https://doi.org/10.1038/374327a0
  24. Benest, A. V. and Augustin, H. G. (2009) Cancer: blood vessels kept quiet. Nature 458, 41-42. https://doi.org/10.1038/458041a
  25. Crawford, Y. and Ferrara, N. (2009) VEGF inhibition: insights from preclinical and clinical studies. Cell Tissue. Res. 335, 261-269. https://doi.org/10.1007/s00441-008-0675-8
  26. Jain, R. K. (2009) A new target for tumor therapy. N. Engl. J. Med. 360, 2669-2671. https://doi.org/10.1056/NEJMcibr0902054
  27. Gutierrez, L. S., Schulman, A., Brito-Robinson, T., Noria, F., Ploplis, V. A. and Castellino, F. J. (2000) Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Cancer Res. 60, 5839-5847.
  28. Healy, A. M. and Gelehrter, T. D. (1994) Induction of plasminogen activator inhibitor-1 in HepG2 human hepatoma cells by mediators of the acute phase response. J. Biol. Chem. 269, 19095-19100.
  29. Illemann, M., Bird, N., Majeed, A., Laerum, O. D., Lund, L. R., Dano, K. and Nielsen, B. S. (2009) Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases. Int. J. Cancer 124, 1860-1870. https://doi.org/10.1002/ijc.24166
  30. Van den Eynden, G. G., Van Laere, S. J., van der Auwera, I., Trinh, X. B., Van Marck, E. A., Dirix, L. Y. and Vermeulen, P. B. (2009) Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases. Int. J. Cancer 125, 1494-1496. https://doi.org/10.1002/ijc.24524

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