Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE154814 | GEO | 2024/07/18
REPOSITORIES: GEO
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Project description:Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability
| PRJNA647822 | ENA
Project description:Glioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and tumor microenvironment. Here, we found that intense infiltration of regulatory T cells (Tregs) facilitated the qualities of GSCs through TGF-β secretion that helped coordinately tumor growth. Mechanistic investigations indicated that TGF-β acted on cancer cells to induce the core cancer stem cell-related genes CD133, SOX2, NESTIN, MUSASHI1 and ALDH1A expression and spheres formation via NF-κB-IL6-STAT3 signaling pathway, resulting in the increased cancer stemness and tumorigenic potential. Furthermore, Tregs promoted glioma tumor growth, and this effect could be abrogated with blockade of IL6 receptor by tocilizumab which also demonstrated certain level of therapeutic efficacy in xenograft model. Additionally, expression levels of CD133, IL6 and TGF-β were found to serve as prognosis markers of glioma patients. Collectively, our findings reveal a new immune-associated mechanism underlying Tregs-induced GSCs. Moreover, efforts to target this network may be an effective strategy for treating glioma.
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Project description:UnlabelledBreast cancers with HER2 overexpression are sensitive to drugs targeting the receptor or its kinase activity. HER2-targeting drugs are initially effective against HER2-positive breast cancer, but resistance inevitably occurs. We previously found that NF-κB is hyperactivated in a subset of HER2-positive breast cancer cells and tissue specimens. In this study, we report that constitutively active NF-κB rendered HER2-positive cancer cells resistant to anti-HER2 drugs and cells selected for lapatinib resistance upregulated NF-κB. In both circumstances, cells were antiapoptotic and grew rapidly as xenografts. Lapatinib-resistant cells were refractory to HER2 and NF-κB inhibitors alone but were sensitive to their combination, suggesting a novel therapeutic strategy. A subset of NF-κB-responsive genes was overexpressed in HER2-positive and triple-negative breast cancers, and patients with this NF-κB signature had poor clinical outcome. Anti-HER2 drug resistance may be a consequence of NF-κB activation, and selection for resistance results in NF-κB activation, suggesting that this transcription factor is central to oncogenesis and drug resistance. Clinically, the combined targeting of HER2 and NF-κB suggests a potential treatment paradigm for patients who relapse after anti-HER2 therapy. Patients with these cancers may be treated by simultaneously suppressing HER2 signaling and NF-κB activation.ImplicationsThe combination of an inhibitor of IκB kinase (IKK) inhibitor and anti-HER2 drugs may be a novel treatment strategy for drug-resistant human breast cancers.
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Project description:BackgroundThe gut microbiota is reportedly involved in the progression and chemoresistance of various human malignancies. However, the underlying mechanisms behind how it exerts some effect on prostate cancer, as an extra-intestinal tumor, in a contact-independent way remain elusive and deserve exploration. Antibiotic exposure, one of the various factors affecting the gut microbiota community and capable of causing gut dysbiosis, is associated with multiple disorders. This study aims to preliminarily clarify the link between gut dysbiosis and prostate cancer.ResultsFirst, we discovered that perturbing the gut microbiota by consuming broad-spectrum antibiotics in water promoted the growth of subcutaneous and orthotopic tumors in mice. Fecal microbiota transplantation could transmit the effect of antibiotic exposure on tumor growth. Then, 16S rRNA sequencing for mouse feces indicated that the relative abundance of Proteobacteria was significantly higher after antibiotic exposure. Meanwhile, intratumoral lipopolysaccharide (LPS) profoundly increased under the elevation of gut permeability. Both in vivo and in vitro experiments revealed that the NF-κB-IL6-STAT3 axis activated by intratumoral LPS facilitated prostate cancer proliferation and docetaxel chemoresistance. Finally, 16S rRNA sequencing of patients' fecal samples revealed that Proteobacteria was enriched in patients with metastatic prostate cancer and was positively correlated with plasma IL6 level, regional lymph node metastasis status, and distant metastasis status. The receiver operating characteristic (ROC) curves showed that the relative abundance of Proteobacteria had better performance than the prostate-specific antigen (PSA) level in predicting the probability of distant metastasis in prostate cancer (area under the ROC curve, 0.860; p < 0.001).ConclusionCollectively, this research demonstrated that gut dysbiosis, characterized by the enrichment of Proteobacteria due to antibiotic exposure, resulted in the elevation of gut permeability and intratumoral LPS, promoting the development of prostate cancer via the NF-κB-IL6-STAT3 axis in mice. Considering findings from human patients, Proteobacteria might act as an intestinal biomarker for progressive prostate cancer. Video Abstract.
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Project description:Expression of the transglutaminase TG2 has been linked to constitutive activation of NF-κB and chemotherapy resistance in mantle cell lymphoma (MCL) cells. TG2 forms complexes with NF-κB components, but mechanistic insights that could be used to leverage therapeutic responses has been lacking. In the current study, we address this issue with the discovery of an unexpected role for TG2 in triggering autophagy in drug-resistant MCL cells through induction of IL6. CRISPR-mediated silencing of TG2 delayed apoptosis while overexpressing TG2 enhanced tumor progression. Under stress, TG2 and IL6 mediate enhanced autophagy formation to promote MCL cell survival. Interestingly, the autophagy product ATG5 involved in autophagosome elongation positively regulated TG2/NF-κB/IL6 signaling, suggesting a positive feedback loop. Our results uncover an interconnected network of TG2/NF-κB and IL6/STAT3 signaling with autophagy regulation in MCL cells, the disruption of which may offer a promising therapeutic strategy. Cancer Res; 76(21); 6410-23. ©2016 AACR.
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Project description:Inflammatory cytokines and lncRNAs are closely associated with tumorigenesis. Herein, we reveal inflammatory cytokines IL6 cooperates with long noncoding RNA CUDR to trigger the malignant transformation of human embryonic stem cells-derived hepatocyte-like stem cells. Mechanistically, IL6 cooperates with CUDR to cause MELLT3 to interact with SUV39h1 mRNA3'UTR and promote SUV39h1 expression. Moreover, the excessive SUV39h1 also increases tri-methylation of histone H3 on nineth lysine (H3K9me3). Intriguingly, under inflammatory conditions, H3K9me3 promotes the excessive expression and phosphorylation of NF-κB, and in turn, phorsphorylated NF-κB promotes the expression and phosphorylation of Stat3. Furthermore, that the phosphorylated Stat3 loads onto the promoter region of miRs and lncRNAs. Ultimately, the abnormal expression of miRs and lncRNAs increased telomerase activity, telomere length and microsatellite instability (MSI), leading to malignant transformation of hepatocyte-like stem cells.
| S-EPMC5104983 | biostudies-literature
Project description:Using a DNA probe from the DNA-binding portion of the NF-IL6 gene and an antibody against the DNA-binding domain of NF-IL6, we isolated a gene homologous to NF-IL6 in the DNA-binding and leucine zipper domains. This intronless gene, termed NF-IL6 beta encodes a 269-amino acid protein with a potential leucine zipper structure, and the gene product can bind to the CCAAT homology as well as the viral enhancer core sequence, as in the cases of NF-IL6 and C/EBP. This gene is expressed at an undetectable or a minor level in normal tissues but is induced by lipopolysaccharide or inflammatory cytokines, as in the case of NF-IL6. NF-IL6 beta easily forms a heterodimer with NF-IL6 in vitro and the heterodimeric complex binds to the same DNA sequence as the respective homodimers. When examined by transient luciferase assays, NF-IL6 beta is consistently a stronger transactivator than NF-IL6. Furthermore, NF-IL6 beta shows a synergistic transcriptional effect with NF-IL6. These data suggest that NF-IL6 beta is an important transcriptional activator in addition to NF-IL6 in regulation of the genes involved in the immune and inflammatory responses.
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Project description:Tumor microenvironment with distinctive cell types and a complex extracellular matrix has a tremendous effect on cancer progression. In the present study we investigated the effects of proinflammatory (M1) and immunosuppressive (M2) macrophages on melanoma cell hyaluronan (HA) metabolism and inflammatory response. M1 macrophages stimulated the formation of a thick pericellular HA matrix in melanoma cells, and the overall HA synthesis was increased due to upregulation of HA synthases (HAS) 1 and 2. HAS2 silencing reversed the effect of M1 CM (conditioned medium) on pericellular HA coat formation, similarly as the chemical inhibitors for TNFR (R-7050), IKK2 (IKK16) and MEK (U0126). RNA sequencing analysis indicated that several inflammation related genes (IL1, IL6, CXCL6) were highly upregulated in M1 CM treated melanoma cells. Gene set enrichment analysis identified that genes related to inflammatory response and TNFα signaling via NF-κB are enriched in M1 CM treated cells. Our results indicate that the activation of MEK and TNFR-NF-κB signaling leads to HAS2 upregulation, while MEK signaling pathway is not involved in cytokine upregulation. Furthermore, HAS2 silencing downmodulated the M1 CM-induced cytokine expression. Our results indicate that proinflammatory macrophages induce an inflammatory response in melanoma cells, where HAS2 upregulation associates with a protumor inflammatory gene signature.
2022-04-26 | GSE178744 | GEO
Project description:The noncanonical NF-κB signaling pathway plays a critical role in a variety of biological functions including chronic inflammation and tumorigenesis. Activation of noncanonical NF-κB signaling largely relies on the abundance as well as the processing of the NF-κB family member p100/p52. Here, TRIM14 is identified as a novel positive regulator of the noncanonical NF-κB signaling pathway. TRIM14 promotes noncanonical NF-κB activation by targeting p100/p52 in vitro and in vivo. Furthermore, a mechanistic study shows that TRIM14 recruits deubiquitinase USP14 to cleave the K63-linked ubiquitin chains of p100/p52 at multiple sites, thereby preventing p100/p52 from cargo receptor p62-mediated autophagic degradation. TRIM14 deficiency in mice significantly impairs noncanonical NF-κB-mediated inflammatory responses as well as acute colitis and colitis-associated colon cancer development. Taken together, these findings establish the TRIM14-USP14 axis as a crucial checkpoint that controls noncanonical NF-κB signaling and highlight the crosstalk between autophagy and innate immunity.
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Project description:This SuperSeries is composed of the following subset Series: GSE27478: Gene expression differences between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice GSE33322: Gene expression analysis between the pancreatic tissues of Pdx1-cre;Kras LSL-G12D and Pdx-cre;KrasLSL-G12D;IKK2/beta F/F mice Refer to individual Series
2012-01-24 | E-GEOD-33323 | biostudies-arrayexpress