Tumor Biology

, Volume 35, Issue 11, pp 11359–11366 | Cite as

Molecular regulation of ovarian cancer cell invasion

  • Ningxia Sun
  • Qing Zhang
  • Chen Xu
  • Qian Zhao
  • Yan Ma
  • Xinmei Lu
  • Liang Wang
  • Wen Li
Research Article

Abstract

The molecular mechanism underlying ovarian cancer invasiveness and metastasis remains unclear. Since significant downregulation in microRNA 200 (miRNA200) family (miR200a, miR200b, and miR200c) has been reported in the invasive ovarian cancer cells, here, we used two human ovarian cancer cell lines, OVCAR3 and SKOV3, to study the molecular basis of miR200, matrix metalloproteinase 3 (MMP3) activation, and cancer invasiveness. We found that overexpression of either miR200 family member in OVCAR3 or SKOV3 cells significantly inhibited production and secretion of MMP3 and cancer invasiveness. Moreover, forced MMP3 expression abolished miR200-induced inhibition of ovarian cancer cell invasiveness, suggesting that miR200 family inhibited ovarian cell invasiveness via downregulating MMP3. Furthermore, ZEB1, a major target of miR200, was inhibited by miR200 overexpression. Forced ZEB1 expression abolished miR200-induced inhibition of ovarian cancer cell invasiveness, suggesting that ZEB1 is a direct target of miR200 for inhibiting ovarian cell invasiveness. Finally, phosphorylated SMAD3 (pSMAD3), a major partner of ZEB1, was efficiently inhibited by miR200, which could be restored by forced expression of ZEB1, but not by forced expression of MMP3, suggesting that ZEB1/pSMAD3 is signaling cascade upstream of MMP3 in this model. Taken together, our data suggest that miR200 family inhibited ovarian cancer cell invasiveness and metastasis by downregulating MMP3, possibly through ZEB1/pSMAD3.

Keywords

Ovarian cancer MiR200 ZEB1 MMP3 SMAD3 

Notes

Conflicts of interest

None

References

  1. 1.
    Dutta DK, Dutta I. Origin of ovarian cancer: molecular profiling. J Obstet Gynaecol India. 2013;63:152–7.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Di Leva G, Croce CM. MiRNA profiling of cancer. Curr Opin Genet Dev. 2013;23:3–11.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Pereira DM, Rodrigues PM, Borralho PM, Rodrigues CM. Delivering the promise of miRNA cancer therapeutics. Drug Discov Today. 2013;18:282–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Feng X, Wang Z, Fillmore R, Xi Y. MiR-200, a new star miRNA in human cancer. Cancer Lett. 2014;344:166–73.PubMedCrossRefGoogle Scholar
  5. 5.
    Shah AA, Leidinger P, Blin N, Meese E. MiRNA: small molecules as potential novel biomarkers in cancer. Curr Med Chem. 2010;17:4427–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Jankovic R, Radulovic S, Brankovic-Magic M. SiRNA and miRNA for the treatment of cancer. J Buon. 2009;14 Suppl 1:S43–9.PubMedGoogle Scholar
  7. 7.
    Leskela S, Leandro-Garcia LJ, Mendiola M, Barriuso J, Inglada-Perez L, Munoz I, et al. The miR-200 family controls beta-tubulin III expression and is associated with paclitaxel-based treatment response and progression-free survival in ovarian cancer patients. Endocr Relat Cancer. 2011;18:85–95.PubMedCrossRefGoogle Scholar
  8. 8.
    Bendoraite A, Knouf EC, Garg KS, Parkin RK, Kroh EM, O'Briant KC, et al. Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial-to-epithelial transition. Gynecol Oncol. 2010;116:117–25.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Hu X, Macdonald DM, Huettner PC, Feng Z, El Naqa IM, Schwarz JK, et al. A miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer. Gynecol Oncol. 2009;114:457–64.PubMedCrossRefGoogle Scholar
  10. 10.
    Jabbari N, Reavis AN, McDonald JF. Sequence variation among members of the miR-200 microRNA family is correlated with variation in the ability to induce hallmarks of mesenchymal-epithelial transition in ovarian cancer cells. J Ovarian Res. 2014;7:12.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Kobayashi M, Salomon C, Tapia J, Illanes SE, Mitchell MD, Rice GE. Ovarian cancer cell invasiveness is associated with discordant exosomal sequestration of Let-7 miRNA and miR-200. J Transl Med. 2014;12:4.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Schmalfeldt B, Prechtel D, Harting K, Spathe K, Rutke S, Konik E, et al. Increased expression of matrix metalloproteinases (MMP)-2, MMP-9, and the urokinase-type plasminogen activator is associated with progression from benign to advanced ovarian cancer. Clin Cancer Res. 2001;7:2396–404.PubMedGoogle Scholar
  13. 13.
    Smolarz B, Szyllo K, Romanowicz-Makowska H, Niewiadomski M, Kozlowska E, Kulig A. PCR analysis of matrix metalloproteinase 3 (MMP-3) gene promoter polymorphism in ovarian cancer. Pol J Pathol. 2003;54:233–8.PubMedGoogle Scholar
  14. 14.
    Szyllo K, Smolarz B, Romanowicz-Makowska H, Niewiadomski M, Kozlowska E, Kulig A. The promoter polymorphism of the matrix metalloproteinase 3 (MMP-3) gene in women with ovarian cancer. J Exp Clin Cancer Res. 2002;21:357–61.PubMedGoogle Scholar
  15. 15.
    Cheng JC, Auersperg N, Leung PC. TGF-beta induces serous borderline ovarian tumor cell invasion by activating EMT but triggers apoptosis in low-grade serous ovarian carcinoma cells. PLoS One. 2012;7:e42436.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Ahn SM, Cha JY, Kim J, Kim D, Trang HT, Kim YM, et al. Smad3 regulates E-cadherin via miRNA-200 pathway. Oncogene. 2012;31:3051–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Nakahata S, Yamazaki S, Nakauchi H, Morishita K. Downregulation of ZEB1 and overexpression of Smad7 contribute to resistance to TGF-beta1-mediated growth suppression in adult T-cell leukemia/lymphoma. Oncogene. 2010;29:4157–69.PubMedCrossRefGoogle Scholar
  18. 18.
    Postigo AA. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J. 2003;22:2443–52.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Xiao X, Wiersch J, El-Gohary Y, Guo P, Prasadan K, Paredes J, et al. TGFbeta receptor signaling is essential for inflammation-induced but not beta-cell workload-induced beta-cell proliferation. Diabetes. 2013;62:1217–26.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Massague J. TGFbeta in cancer. Cell. 2008;134:215–30.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Padua D, Massague J. Roles of TGFbeta in metastasis. Cell Res. 2009;19:89–102.PubMedCrossRefGoogle Scholar
  22. 22.
    Lan HY, Chung AC. Transforming growth factor-beta and Smads. Contrib Nephrol. 2011;170:75–82.PubMedCrossRefGoogle Scholar
  23. 23.
    Tonge DP, Tugwood JD, Kelsall J, Gant TW. The role of microRNAs in the pathogenesis of MMPi-induced skin fibrodysplasia. BMC Genomics. 2013;14:338.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Soubani O, Ali AS, Logna F, Ali S, Philip PA, Sarkar FH. Re-expression of miR-200 by novel approaches regulates the expression of PTEN and MT1-MMP in pancreatic cancer. Carcinogenesis. 2012;33:1563–71.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Ningxia Sun
    • 1
  • Qing Zhang
    • 1
  • Chen Xu
    • 1
  • Qian Zhao
    • 1
  • Yan Ma
    • 1
  • Xinmei Lu
    • 1
  • Liang Wang
    • 1
  • Wen Li
    • 1
  1. 1.Department of Obstetrics and GynecologyShanghai Changzheng Hospital, Second Military Medical UniversityShanghaiChina

Personalised recommendations