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Notch1 enhances NF-κB activation to promote CD133+ Skin Cancer Stem Cells

ABSTRACT: Cancer stem-like cells are hypothesized to be the major tumor initiating cell (TIC) population of human cutaneous squamous cell carcinoma (hcSCC), but the molecular alterations underpinning their cellular phenotype remain undefined. Here, a small CD133+CD31-CD45-CD61-CD24- (CD133+) cell population enriched for self-renewing and TIC features was isolated by sorting from primary hcSCC tumors. CD133+ cells show enhanced spheroid formation in vitro and tumor generation in vivo. Gene expression profiling comparing CD133+ with CD133- cells revealed that CD133+ cells expressed enriched stem cell-like and cancer-related gene signatures. Eighty differentially expressed stem cell-related genes were identified in CD133+ cells, where the top pathways include Notch, Notch1-mediated NF-κB, and WNT signaling. Overexpression of growth factor receptors, PI3K/mTOR, and STAT pathway genes and inactivation of genes regulating epigenetic modification of chromatin implicated in cancer were also identified. Verification of these gene signatures was conducted with Nanostring in an independent tumor set. Pharmacologic or genetic modulation of Notch1, IKKα, RELA and RELB modulated NF-κB transactivation, the CD133+ population, and phenotype. Immunofluorescent staining confirmed co-localization of CD133+ and IKKα expression in SCC tumor specimens. Our data support the linkage and importance of non-canonical Notch1 and IKK-mediated NF-κB activation in promoting CD133+ population and TIC phenotype in hcSCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84588 | GEO | 2019/07/14

REPOSITORIES: GEO

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Homo sapiens

Project description:Notch1 enhances NF-κB activation to promote CD133+ Skin Cancer Stem Cells

| PRJNA330392 | ENA

BRAF-induced tumorigenesis is IKKalpha dependent but NFκB independent

Project description:Tumor cells carrying KRAS mutations activate the NF-κB pathway by different mechanisms, which contribute to the acquisition of essential cancer properties. The BRAF kinase, a downstream mediator of KRAS, is also mutated in a subset of colorectal cancers (CRC), which predicts bad prognosis and therapy resistance. However, nothing is known on whether NF-κB participates of BRAF-mediated tumorigenesis. We here found that in CRC cells, mutant BRAF does not trigger canonical or alternative NF-κB signaling but induces p45-IKKα activation. Moreover, IKKα activity is required for BRAF-induced transformation and to support BRAF-dependent transcription in CRC cells. Activation of p45-IKKα downstream of BRAF requires the TAK1 kinase, and is associated to the endosomal compartment. Inhibition of endosomal V-ATPase abolished p45-IKKα phosphorylation, and induced apoptosis of BRAF mutated CRC cells. Pharmacologic inhibition of endosome acidification reduced the in vivo growth of tumors carrying mutant BRAF, and abrogated the metastatic capacity of a primary human CRC tumor with acquired resistance to standard chemotherapy in an orthotopic xenograft model.

2015-05-08 | GSE57979 | GEO

Targeting the NF-κB signaling pathway in Notch1-induced T cell leukemia

Project description:T cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that the majority of TALL patients carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively-active Notch1 activates the NF-κB pathway transcriptionally and via the IκB kinase (IKK) complex, thereby causing increased expression of multiple well-characterized NF-κB target genes in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-κB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These studies identify NF-κB as one of the major mediators of NOTCH1-induced transformation and suggest that the NF-κB pathway is a potential target of future targeted therapies of T-ALL. Keywords: gene expression analysis, signaling pathway alteration

2006-12-02 | GSE6396 | GEO

TLR4-NFkB-phospho-NF-kB signaling in BMDM

Project description:The model was constructed to describe TLR4 induced NF-κB activation in native bone marrow-derived macrophages. It included processes of ligand (lipopolysaccharide) recognition, formation of dimer receptor complex and further signal transduction through TRAF6/TAK1 complex that leads to the activation of IKKα/β kinase, which in turn enables the NF-κB transcription factor phosphorylation and translocation in the cell nucleus, and induction of IkB and WIP1 (as an example of induced protein that promotes NF-κB dephosphorylation 2) gene transcription. Models were based on the current knowledge of TLR signaling framework, protein interactions within the TLR4 pathway, and up-to-date mathematical models describing Toll receptor activation. The major important additions were made to TLR4 signaling description: 1) Receptor dimerization process 2) The existence of a basal nuclear NF-κB level (translocation) 3) NF-κB phosphorylation by IKK complex

2019-03-27 | MODEL1809230001 | BioModels

Hepatitis C Virus Infection Activates a Novel Innate Pathway Involving IKKα in Lipogenesis and Viral Assembly

Project description:Hepatitis C virus interacts extensively with host factors not only to establish productive infection but also to trigger unique pathological processes. Our recent genome-wide siRNA screen demonstrated that IKKα is a critical host factor for HCV. Here we describe a novel NF-κB-independent and kinase-mediated nuclear function of IKKα in HCV assembly. HCV infection, through its 3’-untranslated region, interacts with DDX3X to activate IKKα, which translocates to the nucleus and induces a CBP/p300-mediated transcriptional program involving SREBPs. This novel innate pathway induces lipogenic genes and enhances core-associated lipid droplet formation to facilitate viral assembly. Chemical inhibitors of IKKα suppress HCV infection and IKKα-induced lipogenesis, offering a proof-of-concept approach for novel HCV therapeutic development. Our results show that HCV commands a novel mechanism to its advantage by exploiting intrinsic innate response and hijacking lipid metabolism, which likely contributes to a high chronicity rate and the pathological hallmark of steatosis in HCV infection. Cells were treated with either non-targeting control siRNA or siRNA against IKKalpha. After 72 h, cells were either mock infected or infected with HCV JFH-1 strain with the M.O.I. of 0.5.

2013-05-08 | E-GEOD-46528 | biostudies-arrayexpress

Treg cell by tumor-associated macrophage ROS and inflammatory signaling through T-cell NF-κB c-Rel drives pathogenesis of lung adenocarcinomas

Project description:IKKα, one subunit of the IKK complex composed of IKKα, IKKβ, and IKKγ (NEMO), is essential for canonical and noncanonical NF-κB pathways involved in the development of lymphoid organs, leukocytes, immunity, and epithelial organs. Deletions of the CHUK locus that encodes IKKα significantly reduce survival for both KRAS-mutation lung adenocarcinoma (ADC) patients and mice, but the question of whether IKKα regulates immune responses remains unanswered. Here, we show that tumor-IKKα reduction elicits an immunosuppressive tumor-microenvironment associated with macrophage and Treg cell induction, which are maintained through elevated reactive oxygen species (ROS) and cytokines important for macrophage and Treg cell development in human and mouse lung ADCs. Enhanced macrophage-ROS and inflammatory cytokine signaling, mediated by tumor-cell IKKα reduction, enforces Treg cell differentiation via a ROS/TNFα/TNFR2/c-Rel pathway in CD4 T-cells. The blockage of each crucial step, including ROS, macrophages, Treg cells, and TNFα/c-Rel, impairs lung ADC development. To explore the molecular mechanism, we performed ChIP-Seq to check some important immunoregulatory genes including TNF, IL-23A CSF1, and CCL22 were regulated transcriptionally by IKKα. Therefore, IKKα serves as a specific surveillant that suppresses immunosuppressive responses and antagonizes lung carcinogenesis in humans and mice.

2022-01-31 | GSE132460 | GEO

Serine/Threonine kinase MLK4 determines Mesenchymal identify in glioma stem cells in an NFkB-dependent manner

Project description:Activation of NF-kB induces MES trans-differentiation and radio-resistance in glioma stem cells (GSCs), but molecular mechanisms for NF-kB activation in GSCs are currently unknown. Here we report that Mixed Lineage Kinase 4 (MLK4) is overexpressed in MES but not PN GSCs. Silencing MLK4 suppresses self-renewal, motility, tumorigenesis, and radio-resistance of MES GSCs via a loss of the MES signature. MLK4 binds and phosphorylates the NF-κB regulator IKKα, leading to activation of NF-κB signaling in GSCs. MLK4 expression is inversely correlated with patient prognosis in MES, but not PN high-grade gliomas. Collectively, our results uncover MLK4 as an upstream regulator of NF-kB signaling and a potential molecular target for the MES subtype of GBMs. We used microarrays to validate MLK4 target gene expression.

2017-09-01 | GSE75224 | GEO

IKKα is essential for the development and maintenance of Marginal zone and Follicular B cells

Project description:IKKα kinase is essential for the B cell maturation and secondary lymphoid organ development. In the current study, we evaluated the role of IKKα in the marginal zone and follicular B lymphocyte development by genetically deleting IKKα from the B cell lineage using CD19-Cre mice. The loss of IKKα did not affect the normal development of early B cell progenitors. However, a significant decline was observed in the percentage of immature B lymphocytes, mature marginal zone and follicular B cells along with a severe disruption of splenic marginal and follicular B cell zones. A gene expression analysis performed on the RNA extracted from the newly formed B cells (B220+IgMhi) revealed that IKKα deficiency produces significant changes in the expression of genes involved in MZ and FO B lymphocyte survival, homing and migration. And several among those genes identified belong to G protein family. Specifically, we validated the upregulated expression of regulator of G protein signaling 13 (RGS13), which is a GTPase activating protein (GAP) that negatively regulates G protein signaling and impede B cell migration. Likewise, promigratory B lymphocyte receptor, the sphingosine-1-phosphate receptor 3 (SIPR3) that couple to Gαi showed significantly reduced expression. In addition, an in silico analysis of gene product interactions revealed NF-κB signaling pathways to be a major gene regulating networks perturbed with IKKα deletion. Taken together, this study reveals IKKαNF-κB and G protein signaling axis to be central for the MZ and FO B cells survival, maintenance, homing and migration.

2017-09-14 | GSE102587 | GEO

Prominin 1/CD133 Endothelium Sustains Growth of Proneural Glioma

Project description:As many other tumors, a subset of gliobastoma is thought to be maintained by a restricted population of cancer cells, stem-like cells that express CD133 transmembrane protein. Expression levels of CD133 gene has been linked to a poor prognostic molecular subgroup and is not overexpressed by the PDGF-driven proneural group. Thus, the significance of CD133+ cells for gliomagenesis of the proneural group is undetermined. In addition, the role of the CD133 protein remains elusive and controversial, which results from the difficult isolation of CD133+ cells that has largely relied on the use of antibodies to ill-defined glycosylated epitopes of CD133. Here, we used a knockin lacZ reporter mouse, Prom1lacZ/+, to track Prom1+ cells in the brain and found that Prom1 (prominin1, murine CD133 homologue) is expressed by cells that co-express markers characteristic of neuronal, glial and vascular lineage phenotype. In proneural tumors derived from injection of RCAS-PDGF into the brain of tv-a;Ink4a-Arf-/- Prom1lacZ/+ mice, Prom1+ cells co-express markers for astrocytes and endothelial cells. Therefore, we characterize the tumor propagation in a murine model and found that the mice co-transplanted with Prom1 endothelium and proneural tumor spheres cells had significant tumor burden and vascular proliferation (angiogenesis). Specific genes in Prom1 endothelium are identified that code for endothelial signaling modulators that most likely support proneural tumor progression and can be potential targets for anti-angiogenic therapy. Cells were sorted via FACS to obtain a population of CD31+CD133- cells and a population of CD31+CD133+ cells. Total RNA was extracted from each population and gene expression was assayed on Affymetrix Mouse 430 2.0 arrays with one array per cell population.

2013-12-31 | E-GEOD-43931 | biostudies-arrayexpress

The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia

Project description:The NF-κB pathway is a critical regulator of the immune system and has been implicated in cellular transformation and tumorigenesis. NF-κB response is regulated by the activation state of the IκB kinase (IKK) complex and triggered by a wide spectrum of stimuli. We previously reported that NF-κB is downstream of Notch1 in T cell acute lymphoblastic leukaemia (T-ALL), however both the mechanisms involving Notch1-induced NF-κB activation and the potential importance of NF-κB in the maintenance of the disease are unknown. Here we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models of this type of leukemia. We show that it is not Notch1 itself but Hes1, a canonical Notch target, the responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by a direct transcriptional repression of the deubiquitinating enzyme CYLD, a well-characterized IKK inhibitor. Consistently, CYLD expression is significantly reduced in primary T-ALL leukemias. Finally, we demonstrate that IKK complex inhibition is a promising option for the targeted therapy of T-ALL as suppression of IKK function affected both the survival of human T-ALL cells in vitro and the maintenance of the disease in vivo. Transcriptional consequences of NF-kB inactivation in human T-ALL1 cell line

2011-05-07 | GSE20667 | GEO

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