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RelB Drives Integrin-Mediated Stress Tolerance and Relapse in High-Grade Serous Ovarian Cancer

ABSTRACT: High-grade serous ovarian cancer (HGSOC) often relapses after chemotherapy due to chemoresistant cancer stem-like cells (CSCs). NF-κB signaling, previously shown to enhance stemness traits, was investigated for its role in post-treatment tumor regrowth. Here, we found that NF-κB subunits RelA and RelB jointly regulate extracellular matrix genes but differentially control integrin subunits: RelA regulates ITGAV (αV) and RelB regulates ITGB3 (β3). Integrin αVβ3 expression is upregulated on CSCs and this is partially driven by NF-κB activation. In vivo models demonstrate that αVβ3⁺ cells have higher tumor-initiating capacity and comprise over 90% of cells from relapsed tumors. Cells expressing RelB and αVβ3 preferentially grow on mesentery at relapse. Targeting this pathway, combined RelB knockdown and inhibition of αVβ3, eliminated stress-tolerant CSCs, reduced tumor burden, and extended survival. These findings highlight integrins as promising therapeutic targets and reveal distinct roles for NF-κB subunits in regulating metastasis and relapse in HGSOC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE334629 | GEO | 2026/06/10

REPOSITORIES: GEO

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RelA and RelB-dependent transcriptome analysis in lymphotoxin-ß receptor stimulated mouse embryonic fibroblasts

Project description:Background: Lymphotoxin signaling via the lymphotoxin-β receptor (LTβR) has been implicated in several biological processes, ranging from development of secondary lymphoid organs, maintenance of splenic tissue, host defense against pathogens, autoimmunity, and lipid homeostasis. The major transcription factor that is activated by LTβR crosslinking is NF-κB. Two signaling pathways have been described that result in the activation of classical p50-RelA and alternative p52-RelB NF-κB heterodimers. Results: Using microarray analysis, we investigated the transcriptional response downstream of the LTβR in mouse embryoni fibroblasts (MEF) and its regulation by the RelA and RelB subunits of NF-κB. We describe novel LTβR-responsive genes that are regulated by RelA and/or RelB. Interestingly, we found that the majority of LTβR-regulated genes require the presence of both RelA and RelB, suggesting significant crosstalk between the two NF-κB activation pathways. Gene Ontology (GO) analysis confirmed that LTβR-NF-κB target genes are predominantly involved in the regulation of immune responses. However, other biological processes, such as apoptosis/cell death, cell cycle, angiogenesis, and taxis were also regulated by LTβR signaling. Moreover, we show that activation of the LTβR inhibits the expression of a key adipogenic transcription factor, peroxisome proliferator activated receptor-γ (pparg), suggesting that LTβR signaling may interfere with adipogenic differentiation. Conclusions: Thus, microarray analysis of LTβR-stimulated fibroblasts revealed further insight into the transcriptional response of LTβR signaling and its regulation by the NF-κB family members RelA and RelB. Keywords: cell type comparison (wt vs relA-/- vs relB-/-) after genetic modification using a time course for each cell type (wt, relA-/-, relB-/-) two time points were analysed (0h as control and 10h) using 3 technical replicates resulting in 18 samples in total

2008-12-17 | E-GEOD-11963 | biostudies-arrayexpress

RelA and RelB-dependent transcriptome analysis in lymphotoxin-ß receptor stimulated mouse embryonic fibroblasts

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AhmedMobeen2021 - NF-kB Activation Model

Project description:NF-kappaB Activation Model includes the activation of both NFKB1:RELA and NFKB2:RELB for Canonical and Non-Canonical Pathway respectively. The model includes the pathway model integrated with post-translational modifications of NF-kB subunits that regulate the NFKB1:RELA and NFKB2:RELB activity. The processes that are regulated by NF-kB pathway can be monitored through following readouts NFKB1:RELA Activity, NFKB2:RELB Activity, Degraded RelA, Degraded RelB, Degraded IkB, Degraded NIK, Apoptosis, Tumour, Antiviral Activity, B Cell Growth and Cell Migration. However, last 5 processes above are also influenced by other pathways too, therefore while making predictions, caution has to be exercised.

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An autoregulatory RelB:p50 NF-κB pathway perpetuates pro-survival TNF response in multiple myeloma

Project description:Pro-inflammatory cytokines were shown to promote growth and survival of cancerous cells. TNF induced RelA:p50 NF-κB dimer via the canonical pathway is thought to link inflammation with cancer. Integrating biochemical and computational studies we identify that deficiency of non-canonical signal transducer p100 triggers a positive autoregulatory loop, which instead perpetuates an alternate RelB:p50 containing NF-κB activity upon TNF treatment. TNF stimulated RelB:p50 dimer is sufficient for mediating NF-κB target gene-expressions and suppressing apoptotic cellular death independent of principal NF-κB subunit RelA. We further demonstrate that activating mutations in non-canonical NF-κB module deplete multiple myeloma cells of p100, thereby, provoking autoregulatory RelB:p50 activation. Finally, autoregulatory control reinforces protracted pro-survival NF-κB response, albeit comprising of RelB:p50, upon TNF priming that protects myeloma cells with dysfunctional p100 from subsequent apoptotic insults. In sum, we present evidence for positive autoregulation mediated through the NF-κB system and its potential involvement in human neoplasm.

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Epigenetic Context Defines the Transcriptional Activity of Canonical and Noncanonical NF-kappaB Signaling in Pancreatic Cancer [RNA-seq]

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