Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132460 | GEO | 2022/01/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Compound heterozygous mutations in the kinase domain of IKKα lead to immunodeficiency and immune dysregulation

Project description:IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. Absence of IKKα cause fetal encasement syndrome in human, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and cause combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were kinase dead mutants. Non-canonical NF-κB activation was abolished in stromal and immune cells while the canonical pathway was partially impaired. Reintroducing wild-type CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of bi-allelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding and suggesting IKKα's role in both NF-κB pathways.

2024-11-24 | GSE267600 | GEO

Impact of G167R mutation in CHUK gene, coding for IKKα protein, on gene expression in PBMCs

Project description:IKKα is a critical regulator of the non-canonical NF-KB signalling pathway. In patients with combined immunodeficiency, we identified a homozygous missense mutation in CHUK gene, coding for IKKα protein, leading to G167R amino acid change in the kinase domain of the protein. This mutation impairs the kinase activity of IKKα, which results in a range of aberratins in innate and adaptive immunity.

2024-10-09 | GSE256535 | GEO

Gene expression alteration by macrophage depletion in IKKα mutant mice

Project description:We generated Ikkα-KA/KA knock-in mice (KA/KA), in which an ATP binding site of Ikkα Lys 44 was replaced by alanine. The knock-in mice develop severe skin lesions and begin to die after 6 to 10 months. We also found lung SCCs in some of the mice. To study lung SCC development, we stabilize the skin condition by crossing KA/KA with Lori.Ikkα transgenic mice to generate KA/KA-Lori.Ikkα mice, which 100% spontaneously developed lethal lung SCC at 4 to 6 months of age. Clodronate-liposomes obtained from Dr. N. van Rooijen (Vrije Universiteit, Amsterdam, Netherlands) were intravenously injected into mice twice every week, started in 4 weeks old mice, and continued for 3 months. The dose of clodronate-liposomes was 100µl during the first month and elevated to 150 100µl after that. The depletion efficacy was confirmed by detecting pulmonary macrophages with Flow Cytometry. Depletion of macrophages in these KA/KA-Lori.Ikkα mice could significantly reduce inflammation and prevent lung SCC developmrnt. This aim of this microarray assay is to identify differentially expressed genes among Wild type, KA/KA-Lori.Ikkα, and macophage-depleted KA/KA-Lori.Ikkα mice, which may highlight the important genes or parthways involved in inflammation-associated lung SCC carcinogenesis. Three samples were analyzed: 1. WT (lung tissue from wild type mouse); 2. KA2 (mixture tissue of lung SCC and tumor neighbor from KA/KA-Lori-Ikkα mouse ); 3. KAT (lung tissue from KA/KA-Lori-Ikkα mouse with macrophage depletion treatment)

2012-04-30 | E-GEOD-37655 | 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:Treg cell by tumor-associated macrophage ROS and inflammatory signaling through T-cell NF-κB c-Rel drives pathogenesis of lung adenocarcinomas

| PRJNA548126 | ENA

Single cell RNA sequencing of paired non small cell lung carcinoma tissue and peripheral blood from 5 donors

Project description:The immunosuppressive tumour microenvironment constitutes a significant hurdle to immune checkpoint inhibitors response. Both soluble factors and specialised immune cells such as regulatory T cells (TReg) are key components of active intratumoural immunosuppression. Previous studies have shown that Inducible Co-Stimulatory receptor (ICOS) can be highly expressed in the tumour microenvironment, especially on immunosuppressive TReg, suggesting that it represents a relevant target for preferential depletion of these cells. Here, we performed immune profiling of samples from paired tumour and peripheral blood of 5 patients with non-small cell lung cancer (NSCLC). We found Icos mRNA expression in NSCLC samples was higher in TRegs than in other T cell subsets and higher in the TME than in the periphery with the expression pattern in both compartments following the general trend of: TReg > CD4non-TReg > CD8 > Other.

2020-09-01 | E-MTAB-9451 | biostudies-arrayexpress

Comparison of gene expression profiling of human lung at four developmental stages and lung adenocarcioma

2014-08-25 | GSE43767 | GEO

Comparison of gene expression profiling of human lung at four developmental stages and lung adenocarcioma

Project description:It is gradually becoming a new aspect in research to search and explore embryo development for malignant information hidden in tumor cells. In this study, the gene expression profiles for human lungs at four developmental stages and lung adenocarcinoma (ADC) were depicted, respectively. The molecular dynamics was compared for development and lung ADC, and it was proposed that primary lung ADC may hijack part of the molecular mechanisms of lung development to down-regulate homeostasis-associated genes and up-regulate stemness-associated genes; and it was revealed that the genes with monotonely decreasing expression trend during lung development process are enriched with lung ADC prognostic information. The study material for developing lung consisted of 29 cases of therapeutic or spontaneous abortion. The samples included whole embryos aged 3 to 5 weeks post ovulation (n = 10, named WholeE), lungs at 6 to 8 postovulatory weeks (PWs) (n = 10, named EarlyL) and lungs at 16 to 24 PWs (n = 9, named MiddleL). WholeE and EarlyL samples were carefully obtained from medical waste with the guidance of a Nikon stereo microscope SMZ1500 (Japan). MiddleL were collected when autopsies were performed. Embryo/Fetuses with known or suspected genetic disorders were excluded. Uninvolved peripheral lung tissue from adults (named MatureL) was obtained from fifteen patients operated on for benign lung diseases. 69 Lung ADC samples used for expression profiling analysis were obtained from patients. All these samples were examined with Agilent Whole Human Genome 4×44k microarray.

2014-08-25 | E-GEOD-43767 | biostudies-arrayexpress

Proteomic Analysis Enables Distinction of Early- Versus Advanced-Stage Lung Adenocarcinomas

Project description:Background: A gel-free proteomic approach was utilized to perform in-depth tissue protein profiling of lung adenocarcinoma (ADC) and normal lung tissues from early and advanced stages of the disease. The long-term goal of this study is to generate a large-scale, label-free proteomic data set from histologically well-classified lung ADC that can be used to increase further our understanding of disease progression and aid in identifying novel biomarkers. Methods and Results: Cases of early-stage (I-II) and advanced-stage (III-IV) lung ADCs were selected and paired with normal lung tissues from 22 patients. The histologically and clinically stratified human primary lung adenocarcinomas were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). From the analysis of ADC and normal specimens, 5,933 protein groups were identified. To examine the protein expression profile of ADC, a peak area-based quantitation method was used. In early- and advanced-stage ADC, 33 and 39 proteins were differentially-expressed respectively between normal and tumor tissue (adjusted p-value < 0.01, fold change ≥ 4). For early- and advanced stage ADC tumors compared to normal patient-matched tissue, 11 and 22 proteins and 23 and 16 proteins were identified as down- and up-regulated, respectively. In silico functional analysis of the up-regulated proteins in both tumor groups revealed that most of the enriched pathways are involved in mRNA metabolism. Furthermore, the most over-represented pathways in the proteins that were unique to ADC are related to mRNA metabolic processes. Conclusions: Further analysis of these data may provide an insight into the molecular pathways involved in disease etiology and may lead to the identification of biomarker candidates and potential targets for therapy. Our study provides potential diagnostic biomarkers for lung ADC and novel stage-specific drug targets for rational intervention.

2021-09-09 | PXD019259 | Pride

Quantitative Phospho-proteomic Analysis of TNFα/NFκB Signaling Reveals a Role for RIPK1 Phosphorylation in Suppressing Necrotic Cell Death

Project description:TNFα is a potent inducer of inflammation due to its ability to promote gene expression, inpart via the NFκB pathway. Moreover, in some contexts, TNFα promotes Caspase-dependent apoptosis or RIPK1/RIPK3/MLKL-dependent necrosis. Engagement of the TNF Receptor Signaling Complex (TNF-RSC), which contains multiple kinase activities, promotes phosphorylation of several downstream components, including TAK1, IKKα/IKKβ, IκBα and NFκB. However, immediate downstream phosphorylation events occurring in response to TNFα signaling are poorly understood at a proteome-wide level. Here we use Tandem mass tagging-based proteomics to quantitatively characterize acute TNFα-mediated alterations in the proteome and phosphoproteome with or without inhibition of the cIAP-dependent survival arm of the pathway with a SMAC mimetic. We identify and quantify over 8,000 phosphorylated peptides, among which are numerous known sites in the TNF-RSC, NFκB, and MAP kinase signaling systems, as well as numerous previously unrecognized phosphorylation events. Functional analysis of S320 phosphorylation in RIPK1 demonstrates a role for this event in suppressing its kinase activity, association with CASPASE-8 and FADD proteins, and subsequent necrotic cell death during inflammatory TNFα stimulation. This study provides a resource for further elucidation of TNFα-dependent signaling pathways.

2017-05-30 | PXD006055 | Pride

Gene expression profiling of paracancerous tissues of human lung squamous cell carcinoma

Project description:Our group previously reported the gene expression profiles of four stages of human lung development, and the expression of one group of genes (PTN1 genes) steadily decreased during lung development, the data included four stages of human lung development and 69 lung adenocarcinoma (ADC) samples, and their gene expression profile data are available in the GEO (GSE43767). Our group has already performed another study with 69 lung squamous cell carcinoma (SCC) tissues, the gene expression profile data are available in the Gene Expression Omnibus (GSE67061). In the present study, we performed the whole genome gene expression mircroarray of 60 paracancerous tissues of human lung squamous cell carcinoma, we aim to show expression characteristics of PTN1 genes during the four lung developmental stages and in lung ADC, lung SCC and paracancerous samples. We examined the prognostic value of the PTN1 genes in five independent lung adenocarcinoma (ADC) and five squamous cell carcinoma (SCC) microarray datasets and revealed that the expression of PTN1 genes was associated with survival in lung ADC patients but had no prognostic value for lung SCC.

2017-07-15 | GSE101420 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data