NF-κB Signaling Modulates miR-452-5p and miR-335-5p Expression to Functionally Decrease Epithelial Ovarian Cancer Progression in Tumor-Initiating Cells

Int J Mol Sci. 2023 Apr 25;24(9):7826. doi: 10.3390/ijms24097826.


Epithelial ovarian cancer (EOC) remains the fifth leading cause of cancer-related death in women worldwide, partly due to the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that promote disease relapse. We previously described a role for the NF-κB pathway in promoting TIC chemoresistance and survival through NF-κB transcription factors (TFs) RelA and RelB, which regulate genes important for the inflammatory response and those associated with cancer, including microRNAs (miRNAs). We hypothesized that NF-κB signaling differentially regulates miRNA expression through RelA and RelB to support TIC persistence. Inducible shRNA was stably expressed in OV90 cells to knockdown RELA or RELB; miR-seq analyses identified differentially expressed miRNAs hsa-miR-452-5p and hsa-miR-335-5p in cells grown in TIC versus adherent conditions. We validated the miR-seq findings via qPCR in TIC or adherent conditions with RELA or RELB knocked-down. We confirmed decreased expression of hsa-miR-452-5p when either RELA or RELB were depleted and increased expression of hsa-miR-335-5p when RELA was depleted. Either inhibiting miR-452-5p or mimicking miR-335-5p functionally decreased the stem-like potential of the TICs. These results highlight a novel role of NF-κB TFs in modulating miRNA expression in EOC cells, thus opening a better understanding toward preventing recurrence of EOC.

Keywords: NF-κB; RELA; RELB; epithelial ovarian cancer; miR-335-5p; miR-452-5p.

MeSH terms

  • Carcinoma, Ovarian Epithelial / genetics
  • Cell Line, Tumor
  • Female
  • Humans
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasm Recurrence, Local
  • Ovarian Neoplasms* / genetics


  • MicroRNAs
  • MIRN335 microRNA, human
  • MIRN452 microRNA, human
  • NF-kappa B
  • RELA protein, human
  • RELB protein, human