MiR-744-5p inducing cell death by directly targeting HNRNPC and NFIX in ovarian cancer cells

Sci Rep. 2018 Jun 13;8(1):9020. doi: 10.1038/s41598-018-27438-6.

Abstract

MicroRNAs (miRNAs) play an important role in the regulation of gene expression. The binding to target messenger RNAs (mRNAs) results in mRNA cleavage or inhibition of the translational machinery leading to decreased protein levels. Various signalling pathways, including apoptosis are modulated by miRNAs. Here, we investigated the role of miR-744-5p in apoptosis signalling in ovarian cancer cell lines. MiR-744-5p expression was reduced in the cancer cell lines independent of the host gene MAP2K4. Overexpression of miR-744-5p activated the intrinsic apoptotic pathway in SKOV3, OVCAR3 and Cisplatin resistant (A2780-cis) and non-resistant A2780 cells leading to cell death. Notably, miR-744-5p overexpression together with Carboplatin treatment led to at least additive pro-apoptotic effects. Investigation of the apoptotic signalling pathways mediated by miR-744-5p revealed that its elevated expression directly downregulated mRNA and protein expression of nuclear factor I X (NFIX) and heterogeneous nuclear ribonucleoprotein C (HNRNPC). HNRNPC caused diminished miR-21 expression and AKT phosphorylation, while NFIX decreased Bcl2 levels, leading to the detected pro-apoptotic effects. Finally, Kaplan-Meier-Plots showed a prolonged median disease-free survival in ovarian serous cystadenocarcinoma patients with high miR-744 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Carboplatin / administration & dosage
  • Carboplatin / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cystadenocarcinoma, Serous / drug therapy
  • Cystadenocarcinoma, Serous / genetics*
  • Cystadenocarcinoma, Serous / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • HEK293 Cells
  • Heterogeneous-Nuclear Ribonucleoprotein Group C / genetics*
  • Heterogeneous-Nuclear Ribonucleoprotein Group C / metabolism
  • Humans
  • Kaplan-Meier Estimate
  • MicroRNAs / genetics*
  • Middle Aged
  • NFI Transcription Factors / genetics*
  • NFI Transcription Factors / metabolism
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism

Substances

  • HNRNPC protein, human
  • Heterogeneous-Nuclear Ribonucleoprotein Group C
  • MIRN744 microRNA, human
  • MicroRNAs
  • NFI Transcription Factors
  • NFIX protein, human
  • Carboplatin