Proteasome inhibitor-resistant cells cause EMT-induction via suppression of E-cadherin by miR-200 and ZEB1

  • Authors:
    • Tadashi Asakura
    • Noriko Yamaguchi
    • Kiyoshi Ohkawa
    • Kiyotsugu Yoshida
  • View Affiliations

  • Published online on: March 4, 2015     https://doi.org/10.3892/ijo.2015.2916
  • Pages: 2251-2260
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Abstract

Downregulation of E-cadherin (gene: CDH1) plays an important role in epithelial-mesenchymal transition (EMT), which is critical for normal development and disease states. As a result of long-term treatment of endometrial carcinoma Ishikawa cells with epoxomicin (EXM), the cells exhibited the phenotype for EXM-resistance (Ish/EXM cells). Moreover, CDH1 mRNA and its protein were suppressed and EMT was induced in Ish/EXM cells. Ish/EXM cells exhibited drug-resistance to other proteasome inhibitors, MG-132, PSI and PS-341 (Bortezomib). The proteasome inhibitor-resistant cells acquired invasiveness as a result of the chemotherapy. In Ish/EXM cells, E-cadherin was suppressed by upregulation of its transcriptional repressor ZEB1. Furthermore, expression of the miR-200 family (miR-200a, miR-200b, miR-200c and miR-141) found in Ishikawa cells was suppressed in Ish/EXM cells. Overexpression of the miR-200 family in Ish/EXM cells caused by transfection with the pre-miR-200 family induced downregulation of ZEB1 and enhanced expression of E-cadherin. Conversely, suppression of miR-200 expression in the Ishikawa cells by transfection with anti-miR-200 elevated the expression of ZEB1 and suppressed the expression of E-cadherin. These results suggest that acquirement of EXM-resistance in Ish/EXM cells induces up regulation of ZEB1 via suppression of the miR-200 family following suppression of E-cadherin. Since suppression of ZEB1 in Ish/EXM cells by treatment with its siRNA did not restore the miR-200 family expression, miR-200 family was placed upstream of ZEB1 to regulate the expression.
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May-2015
Volume 46 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Asakura T, Yamaguchi N, Ohkawa K and Yoshida K: Proteasome inhibitor-resistant cells cause EMT-induction via suppression of E-cadherin by miR-200 and ZEB1. Int J Oncol 46: 2251-2260, 2015.
APA
Asakura, T., Yamaguchi, N., Ohkawa, K., & Yoshida, K. (2015). Proteasome inhibitor-resistant cells cause EMT-induction via suppression of E-cadherin by miR-200 and ZEB1. International Journal of Oncology, 46, 2251-2260. https://doi.org/10.3892/ijo.2015.2916
MLA
Asakura, T., Yamaguchi, N., Ohkawa, K., Yoshida, K."Proteasome inhibitor-resistant cells cause EMT-induction via suppression of E-cadherin by miR-200 and ZEB1". International Journal of Oncology 46.5 (2015): 2251-2260.
Chicago
Asakura, T., Yamaguchi, N., Ohkawa, K., Yoshida, K."Proteasome inhibitor-resistant cells cause EMT-induction via suppression of E-cadherin by miR-200 and ZEB1". International Journal of Oncology 46, no. 5 (2015): 2251-2260. https://doi.org/10.3892/ijo.2015.2916