Expression of miR-224-5p is associated with the original cisplatin resistance of ovarian papillary serous carcinoma

Oncol Rep. 2014 Sep;32(3):1003-12. doi: 10.3892/or.2014.3311. Epub 2014 Jul 7.

Abstract

Chemoresistance is a major challenge to successful chemotherapy of ovarian cancer, which represents the leading cause of mortality from gynecologic malignancies. We demonstrated that overexpression of miR-224-5p in ovarian cancer patients is associated with platinum-based chemoresistance using miRNA microarray analysis and quantitative real-time polymerase chain reaction (qRT-PCR) validation in vivo, as well as in 4 human ovarian cancer cell lines (C13/OV2008; A2780CP/A2780S) in vitro. In the present study, we aimed to clarify the role of miR-224-5p in regulating the chemoresistance of ovarian cancer. By using the sensitive miRNA transient transfection, we demonstrated expression and bioactivity of miR-224-5p in ovarian cancer cell lines. It is of note that enforced expression of miR-224-5p enhanced chemoresistance to cisplatin in ovarian cancer cells through apoptosis reversion. We predicted and identified the PRKCD gene as one of the targets of miR-224-5p in mediating the primary chemoresistance of ovarian cancer patients. We showed reciprocal expression of miR-224-5p and PRKCD by quantitative analysis in complete response and incomplete response patients in vivo, and 2 pairs of cisplatin resistance and sensitive cell lines in vitro, after either miR-224-5p overexpression or knockdown transfection. Additionally, miR-224-5p and PRKCD can serve as novel predictors and prognostic biomarkers for ovarian papillary serous carcinoma (OPSC) patient response to overall disease-specific survival. Our findings suggest that miR-224-5p may function as an oncogene and induce platinum resistance in OPSC at least in part by downregulating PRKCD, thereby providing a biomarker for predicting chemosensitivity to cisplatin in patients with ovarian cancer.

MeSH terms

  • Cell Line, Tumor
  • Cisplatin / therapeutic use
  • Cystadenocarcinoma, Serous / drug therapy
  • Cystadenocarcinoma, Serous / genetics*
  • Cystadenocarcinoma, Serous / pathology
  • Down-Regulation
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Profiling
  • Humans
  • In Vitro Techniques
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Middle Aged
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Protein Kinase C-delta / genetics
  • Protein Kinase C-delta / metabolism*
  • Survival Analysis

Substances

  • MIRN224 microRNA, human
  • MicroRNAs
  • PRKCD protein, human
  • Protein Kinase C-delta
  • Cisplatin