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Effect of the depletion of NR4A1 on gene expression in PNET cell line QGP-1

ABSTRACT: Pancreatic neuroendocrine tumours (PNETs) are rare neuroendocrine cancers with high mortality rates and an immense unmet medical need. While the genetic and immune landscape of PNETs is defined, the molecular mechanisms linking these factors to tumorigenesis remain poorly understood. Here, we identify NF-κB as an oncogenic driver in PNETs, regulated through both cancer cell extrinsic and intrinsic mechanisms. CellChat analysis revealed M2-like tumour-associated macrophages as the dominant source of NF-κB-activating cytokines within the PNET microenvironment. Concurrently, we uncover a cancer cell intrinsic safeguard mechanism wherein the tumour suppressor menin associates with RelA to suppress PNET growth. Molecular docking identified key residues mediating the menin-RelA interaction and revealed three clinically relevant menin mutants (P320R, R415P, W423R) that destabilize this complex, thereby compromising menin’s ability to suppress PNET growth. Mechanistically, menin and RelA co-bind κB sites in the promoters of proliferation-associated NF-κB target genes, including NR4A1, to silence their expression. Importantly, NR4A1 depletion markedly reduces PNET growth in vitro and in vivo, underscoring its functional role in PNET tumorigenesis. Together, our findings reveal a novel menin-RelA-NR4A1 axis that regulates PNET growth and demonstrates how extrinsic and intrinsic factors converge on NF-κB signaling to drive PNET progression, revealing potential avenues for therapeutic intervention

ORGANISM(S): Homo sapiens

PROVIDER: GSE308223 | GEO | 2026/09/17

REPOSITORIES: GEO

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Menin-RelA complex antagonizes cancer cell-intrinsic and tumour microenvironment-induced NF-κB hyperactivation to suppress pancreatic neuroendocrine tumorigenesis

Project description:Pancreatic neuroendocrine tumours (PNETs) are rare neuroendocrine cancers with high mortality rates and an immense unmet medical need. While the genetic and immune landscape of PNETs is defined, the molecular mechanisms linking these factors to tumorigenesis remain poorly understood. Here, we identify NF-κB signaling as a key effector pathway that contributes to PNET tumorigenesis, regulated through both cancer cell extrinsic and intrinsic mechanisms. CellChat analysis identifies M2-like macrophages as the dominant source of NF-κB-activating cytokines, and co-culture of PNET cancer cells with THP-1-derived M2-macrophages significantly enhances RelA phosphorylation and colony-forming capacity in vitro. Concurrently, we uncovered a cancer cell intrinsic safeguard mechanism wherein the tumour suppressor menin physically associates with RelA to suppress PNET growth in vitro and in vivo. Molecular docking identified key residues mediating the menin-RelA interaction and revealed three clinically relevant menin mutants (P320R, R415P, W423R) that destabilize this complex, compromising menin’s ability to restrain PNET growth. Mechanistically, menin and RelA co-bind κB sites on promoters of proliferation-associated NF-κB target genes, including NR4A1, and epigenetically silence their expression through reduced H3K27ac. Crucially, NR4A1 depletion or small-molecule inhibition suppresses PNET growth in vitro and in vivo. Together, our findings reveal a novel menin-RelA-NR4A1 axis that regulates PNET growth and demonstrates how extrinsic and intrinsic factors converge on NF-κB signaling, highlighting potential therapeutic avenues.

2026-07-11 | GSE326578 | GEO

Menin-RelA complex antagonizes cancer cell-intrinsic and tumor microenvironment-induced NF-κB hyperactivation to suppress pancreatic neuroendocrine tumorigenesis

Project description:Pancreatic neuroendocrine tumors (PNETs) are rare neuroendocrine cancers with high mortality rates and an immense unmet medical need. While the genetic and immune landscape of PNETs is defined, the molecular mechanisms linking these factors to tumorigenesis remain poorly understood. Here, we identify NF-κB signaling as a key effector pathway that contributes to PNET tumorigenesis, regulated through both cancer cell extrinsic and intrinsic mechanisms. CellChat analysis identifies M2-like macrophages as the dominant source of NF-κB-activating cytokines, and co-culture of PNET cancer cells with THP-1-derived M2-macrophages significantly enhances RelA phosphorylation and colony-forming capacity in vitro. Concurrently, we uncovered a cancer cell intrinsic safeguard mechanism wherein the tumor suppressor menin physically associates with RelA to suppress PNET growth in vitro and in vivo. Molecular docking identified key residues mediating the menin-RelA interaction and revealed three clinically relevant menin mutants (P320R, R415P, W423R) that destabilize this complex, compromising menin’s ability to restrain PNET growth. Mechanistically, menin and RelA co-bind κB sites on promoters of proliferation-associated NF-κB target genes, including NR4A1, and epigenetically silence their expression through reduced H3K27ac. Crucially, NR4A1 depletion or small-molecule inhibition suppresses PNET growth in vitro and in vivo. Together, our findings reveal a novel menin-RelA-NR4A1 axis that regulates PNET growth and demonstrates how extrinsic and intrinsic factors converge on NF-κB signaling, highlighting potential therapeutic avenues.

2026-07-11 | GSE329027 | GEO

Differentially expressed genes upon the overexpression of MENIN in QGP1 cells

Project description:Pancreatic neuroendocrine tumours (PNETs) are graded based on their proliferation rate marked by Ki-67, where increased proliferation is associated with poorer prognosis. However, detailed molecular mechanisms underlying their proliferation remain to be clarified. In this study, we have identified NF-κB signalling as a novel pathway that is hyperactivated in PNETs via single cell analyses and immunofluorescence staining of human PNET tissues. Furthermore, we have confirmed that the NF-κB subunit RelA/p65 is implicated in PNET proliferation in vitro and in vivo and demonstrated that depleting or inhibiting RelA/p65 significantly reduces the proliferation rate of QGP-1 cells. Separately, we have uncovered that menin (encoded by the MEN1 gene), a tumour suppressor commonly mutated in PNETs, represses PNET proliferation in a RelA/p65-dependent manner, by downregulating the expression of RelA/p65 target genes associated with proliferation. We have identified the NR4A1 gene as one such target and confirmed that its expression is highly upregulated in MEN1 mutated PNETs. Additionally, the depletion or chemical inhibition of NR4A1 significantly reduced cellular proliferation. Therefore, serving as a proof of concept that RelA/p65 target genes such as NR4A1 is implicated in PNET proliferation and can be targeted for therapeutic treatment. Overall, our study has identified the NF-κB signalling pathway and a subset of its genes such as NR4A1 to be responsible for PNET proliferation, opening new potential therapeutic options for both PNETs and MEN1-mutated PNETs.

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2015-11-30 | E-MTAB-3596 | biostudies-arrayexpress

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

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2020-10-03 | E-MTAB-7889 | biostudies-arrayexpress

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A pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics

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