Dataset Information

NF-κB and STAT3 signaling uniquely stratifies survival in female glioblastoma patients

ABSTRACT: Sex differences in glioblastoma (GBM) incidence, prognosis, and response to treatment are well established. However, the molecular mechanisms that drive these differences are less well understood. In a pan-cancer study, we previously reported that female patients exhibit a sex bias towards upregulated inflammatory signaling across many cancers. Additionally, upregulated nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling in GBM is associated with poor survival. Here, we report that only female GBM patients with higher expression of NF-κB- or IL6/JAK/STAT3-related genes have poorer survival compared to females with lower expression, a pattern not seen in male patients. Interestingly this sex difference was only evident in GBM tumors with wild-type epidermal growth factor receptor (EGFR). Using a mouse GBM model, we report that female GBM cells have similar stronger signatures in NF-κB and STAT3 signaling and exhibit a more robust response to manipulation of both pathways. Furthermore, female cells exhibited a stronger relationship between STAT3 activity and its sensitivity towards STAT3 inhibition. These results demonstrate that targeting NF-κB and STAT3 signaling in a sex-informed manner in GBM patients with wild-type EGFR tumors may improve patient response to treatment. Overall, this study highlights the mechanistic and clinical importance of analyzing data that is disaggregated by sex.

ORGANISM(S): Mus musculus

PROVIDER: GSE295851 | GEO | 2026/01/13

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Rationale：Glioblastoma (GBM) is a highly aggressive brain tumor, often associated with the activation of EGFR and NF-κB signaling pathways in radioresistant GBM cells. Concurrently targeting these pathways presents a promising strategy to overcome radioresistance and enhance therapeutic efficacy. Methods：We established a radioresistant glioblastoma stem cell (GSCs) model by exposing U87-derived GSCs to 5 Gy irradiation for 13 cycles. After differentiation and colony formation selection, we obtained a radioresistant cell line (Diff cells). These model cell lines mimic the progression of recurrence in GBM. Transcriptomic analysis of Diff cells, GSCs, and U87 cells, combined with public datasets from The Cancer Genome Atlas (TCGA), was conducted to identify key signaling pathways involved in radioresistance. Based on these findings, we designed a novel dual-functionalized nanoliposome (iRGD-OB-LP) for the co-delivery of Osimertinib and Bortezomib to simultaneously inhibit the EGFR and NF-κB pathways. The physicochemical properties, cellular uptake, and drug release profiles of iRGD-OB-LP were characterized, and its targeting capability, antitumor activity, and radiosensitization potential were evaluated both in vitro and in vivo. Results: We successfully established GSCs from U87 cells and induced radioresistance in these GSCs. The Diff cells derived from GSCs retained radioresistant characteristics and exhibited significant resistance to radiotherapy-induced cell death. Transcriptomic analysis of Diff cells, GSCs, and U87 cells, along with TCGA data, identified EGFR and NF-κB (RelA/p65) as key pathways involved in radioresistance. iRGD-OB-LP demonstrated efficient tumor-specific targeting, cellular uptake, and sustained drug release. In vitro, iRGD-OB-LP effectively inhibited EGFR and NF-κB pathway activation, prolonged DNA damage induced by radiotherapy, reduced tumor cell stemness, and enhanced radiotherapy-induced apoptosis. In vivo, studies using an orthotopic GBM mouse model revealed that iRGD-OB-LP successfully crossed the blood-tumor barrier, accumulated at tumor sites, and synergistically enhanced the efficacy of radiotherapy, as evidenced by suppressed tumor growth and prolonged survival. Conclusion: In this study, we established Diff cells as a radioresistant model derived from GSCs and identified EGFR and NF-κB (RelA/p65) as critical pathways in sustaining the radioresistant phenotype through RNA sequencing and TCGA data analysis. The iRGD-OB-LP nanoplatform offers a promising strategy for targeted delivery of dual inhibitors to simultaneously inhibit EGFR and NF-κB, overcoming GBM radioresistance. This innovative approach highlights a potential strategy to improve radiotherapy outcomes in GBM treatment.

Project description:Mitochondrial DNA depleted (ρ(0)) human skin fibroblasts (HSF) with suppressed oxidative phosphorylation were characterized by significant changes in the expression of 2100 nuclear genes, encoding numerous protein classes, in NF-κB and STAT3 signaling pathways, and by decreased activity of mitochondrial death pathway, compared to the parental ρ(+) HSF. In contrast, the extrinsic TRAIL/TRAIL-Receptor mediated death pathway remained highly active, and exogenous TRAIL in a combination with cycloheximide (CHX) induced higher levels of apoptosis in ρ(0) cells compared to ρ(+) HSF. Global gene expression analysis using microarray and qRT-PCR demonstrated that mRNA expression levels of many growth factors and their adaptor proteins (FGF13, HGF, IGFBP4, IGFBP6, and IGFL2), cytokines (IL6, ΙL17Β, ΙL18, ΙL19, and ΙL28Β) and cytokine receptors (IL1R1, IL21R, and IL31RA) were substantially decreased after mitochondrial DNA depletion. Some of these genes were targets of NF-κB and STAT3, and their protein products could regulate the STAT3 signaling pathway. Alpha-irradiation further induced expression of several NF-κB/STAT3 target genes, including IL1A, IL1B, IL6, PTGS2/COX2 and MMP12, in ρ(+) HSF, but this response was substantially decreased in ρ(0) HSF. Suppression of the IKK-NF-κB pathway by the small molecular inhibitor BMS-345541 and of the JAK2-STAT3 pathway by AG490 dramatically increased TRAIL-induced apoptosis in the control and irradiated ρ(+) HSF. Inhibitory antibodies against IL6, the main activator of JAK2-STAT3 pathway, added into the cell media, also increased TRAIL-induced apoptosis in HSF, especially after alpha-irradiation. Collectively, our results indicated that NF-κB activation was partially lost in ρ(0) HSF resulting in downregulation of the basal or radiation-induced expression of numerous NF-κB targets, further suppressing IL6-JAK2-STAT3 that in concert with NF-κB regulated protection against TRAIL-induced apoptosis.

Dataset Information

NF-κB and STAT3 signaling uniquely stratifies survival in female glioblastoma patients

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets