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

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-?B pathway in promoting TIC chemoresistance and survival through NF-?B 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-?B 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-?B TFs in modulating miRNA expression in EOC cells, thus opening a better understanding toward preventing recurrence of EOC.

Automated summary

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-related death in women worldwide, and chemoresistant, stem-like tumor-initiating cells (TICs) contribute to disease relapse. The NF-κB pathway and its transcription factors (RelA and RelB) have been found to promote TIC survival and chemoresistance. This study demonstrates that NF-κB signaling differentially regulates miRNA expression through RelA and RelB in EOC cells, and the miRNAs, hsa-miR-452-5p and hsa-miR-335-5p, play a role in TIC persistence. These findings provide new insights into preventing EOC recurrence.