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

Abstract

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.

Drug resistance in ovarian cancer: from mechanism to clinical trial

“…Moreover, NF-κB p65 increases miR-200b/c expression by binding to its promoter, subsequently sensitizing ovarian cancer cells to cisplatin [ 100 ]. It also regulates the downstream miRNAs miR-452-5p and miR-335-5p through the NF-κB TFs RelA and RelB, preventing the recurrence of OC [ 101 ]. Moreover, the NF-κB signaling pathway has been implicated in immunosuppression and immune evasion in ovarian cancer cells partly via NFκB-dependent production of IL-6, which impairs DCs but generates and recruits immunosuppressive MDSCs, and IL-8, which increases the expression of the immunosuppressive enzyme arginase [ 102 ].…”

High-Mobility Group Box 1 Overexpression Predicts a Poor Prognosis and Promotes Epithelial-Mesenchymal Transition in Gastric Cancer by Activating TLR4/NF-κB Signaling

“…Studies have suggested that the NF-κB signaling pathway plays a critical role in promoting tumor development [14][15][16]. Changes in the TLR4/NF-κB signaling pathway were further investigated following alterations in HMGB1 expression.…”