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miR-141 regulates KEAP1 and modulates cisplatin sensitivity in ovarian cancer cells

M T M van Jaarsveld1, J Helleman, A W M Boersma

  • 1Department of Medical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.

Oncogene
|October 10, 2012
PubMed

Insights

MicroRNAs (miRNAs) like miR-141 contribute to cisplatin resistance in ovarian cancer by targeting KEAP1. This regulation impacts the NF-κB pathway, affecting treatment response in non-serous tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Epithelial ovarian cancer is a leading cause of gynecological cancer deaths.
  • Drug resistance significantly impedes effective ovarian cancer treatment.
  • The role of microRNAs (miRNAs) in ovarian cancer drug resistance remains underexplored.

Purpose of the Study:

  • To investigate the role of microRNAs in cisplatin resistance in epithelial ovarian cancer.
  • To identify specific miRNAs associated with cisplatin sensitivity and resistance.
  • To elucidate the molecular mechanisms underlying miRNA-mediated drug resistance.

Main Methods:

  • Comparative miRNA expression profiling of cisplatin-sensitive and -resistant ovarian cancer cell lines.
  • Correlation analysis of miRNA expression with cisplatin sensitivity in the NCI-60 panel and primary ovarian tumors.
  • Functional studies involving miRNA overexpression and KEAP1 manipulation.
  • Luciferase reporter assays to confirm direct targeting of KEAP1 by miR-141.
  • Investigation of the NF-κB pathway activation.

Main Results:

  • 27 miRNAs were differentially expressed between sensitive and resistant cell lines, with miR-141/200c family members showing correlation with cisplatin sensitivity.
  • Overexpression of miR-141 increased cisplatin resistance in ovarian cancer cells.
  • Higher miR-141 levels in non-serous ovarian tumors correlated with poor response to platinum-based chemotherapy.
  • miR-141 directly targets KEAP1, and its downregulation induces cisplatin resistance.
  • KEAP1 downregulation activates the NF-κB pathway, contributing to cisplatin resistance.

Conclusions:

  • miR-141 plays a significant role in mediating cisplatin resistance in epithelial ovarian cancer.
  • The miR-141-KEAP1 axis is a key regulator of cellular response to cisplatin.
  • Targeting the miR-141-KEAP1 pathway may offer novel therapeutic strategies for overcoming drug resistance in ovarian cancer.

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