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Genome-wide ChIP-Seq analysis of genomic Stat3 binding sites in murine gastric tumors following stimulation with IL6 or IL11 (MACS)

ABSTRACT: The latent transcription factor STAT3 is a point of convergence for numerous oncogenic signaling pathways and is excessively activated in the majority of human epithelial cancers. STAT3 promotes many hallmarks of cancer including enhanced proliferation, increased survival, sustained angiogenesis, immune evasion and tumor-promoting inflammation. We performed chromatin immunoprecipitations (ChIP) followed by next-generation sequencing (ChIP-Seq) to identify genomic Stat3 binding sites in established gastric tumors of gp130F/F mutant mice (Tebbutt et al., 2002) following administration of recombinant human interleukin (IL)-6 or IL11. The study was designed to assess differences in Stat3 recruitment in response to IL6 and IL11, two cytokines which both activate Stat3 through the shared IL6 cytokine family receptor subunit gp130. In gp130F/F mice, a robust model for inflammation-associated intestinal-type gastric tumorigenesis, the Y757F knock-in mutation in the gp130 receptor triggers spontaneous gastric tumor formation in a strictly IL11-dependent manner, but independent of IL6 signaling (Ernst et al., 2008). Therefore, the study aimed to identify IL6- and IL11-specific Stat3 target genes. In total, we identified 948 or 961 significant Stat3-DNA interactions in gp130F/F tumors following IL6 or IL11 administration, respectively. These interactions were validated by binding motif analysis which showed that at least 30% of all Stat3-associated genomic regions comprise a Stat3 consensus binding sequence.

ORGANISM(S): Mus musculus

PROVIDER: GSE48285 | GEO | 2015/10/01

SECONDARY ACCESSION(S): PRJNA209519

REPOSITORIES: GEO

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Genome-wide ChIP-Seq analysis of genomic Stat3 binding sites in murine gastric tumors following stimulation with IL6 or IL11 (CisGenome)

Project description:The latent transcription factor STAT3 is a point of convergence for numerous oncogenic signaling pathways and is excessively activated in the majority of human epithelial cancers. STAT3 promotes many hallmarks of cancer including enhanced proliferation, increased survival, sustained angiogenesis, immune evasion and tumor-promoting inflammation. We performed chromatin immunoprecipitations (ChIP) followed by next-generation sequencing (ChIP-Seq) to identify genomic Stat3 binding sites in established gastric tumors of gp130F/F mutant mice (Tebbutt et al., 2002) following administration of recombinant human interleukin (IL)-6 or IL11. The study was designed to assess differences in Stat3 recruitment in response to IL6 and IL11, two cytokines which both activate Stat3 through the shared IL6 cytokine family receptor subunit gp130. In gp130F/F mice, a robust model for inflammation-associated intestinal-type gastric tumorigenesis, the Y757F knock-in mutation in the gp130 receptor triggers spontaneous gastric tumor formation in a strictly IL11-dependent manner, but independent of IL6 signaling (Ernst et al., 2008). Therefore, the study aimed to identify IL6- and IL11-specific Stat3 target genes. In total, we identified 948 or 961 significant Stat3-DNA interactions in gp130F/F tumors following IL6 or IL11 administration, respectively. These interactions were validated by binding motif analysis which showed that at least 30% of all Stat3-associated genomic regions comprise a Stat3 consensus binding sequence.

2015-10-01 | GSE48287 | GEO

Genome-wide analysis of interleukin (IL) -6 and IL-11 responsive genes in murine gastric tumors

Project description:We performed micrarrays to analyse gene expression in spontaneously arising gastric tumors from gp130Y757F/F mutant mice (Tebbutt et al., 2002) following administration of recombinant human IL-6 or IL-11. The present study was designed to assess differences in gene expression in response to IL-6 and IL-11, two cytokines which both activate the shared gp130 receptor and downstream Stat3 signalling pathway. Since gastric tumorigenesis in gp130Y757F/F mice is strictly dependent on IL-11, but not IL-6 signalling (Ernst et al., 2008) the study aimed to identify IL-6 and IL-11 specific target genes which may account for the IL-11 dependent tumor development. Total RNA was obtained from gastric tumor tissue of gp130Y575F/F mice collected 60 min after a single systemic (i.p.) administration of PBS (vehicle control), recombinant human IL6 or IL11 (5 ug). The gene expression profile of the IL-6 and IL-11 treated samples were separately compared to the PBS (vehicle) treated control samples, resulting in two lists of responsive genes (”IL-6 vs control” and “IL-11 vs control”).

2013-08-10 | E-GEOD-43800 | biostudies-arrayexpress

IL11 is elevated in systemic sclerosis and IL11-dependent ERK signaling is needed for the profibrotic activity of TGFβ in dermal fibroblasts

Project description:Objectives: Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with human dermal fibroblast (HDF) activation. Methods: We measured serum IL11 levels in healthy volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches. Results: In patients with SSc, serum IL11 levels are elevated as compared to healthy controls. Transforming growth factor beta (TGFβ) isoforms 1, 2 or 3 induced IL11 secretion from HDFs, which highly express IL11RA and the gp130 co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 consistently and robustly stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation. IL11 induced STAT phosphorylation to a lesser extent than ERK and only at high IL11 concentrations. IL11-stimulated ERK activation and fibrosis phenotypes were absent in skin fibroblasts from patients with homozygous loss-of-function mutation in IL11RA. Inhibition of IL11 signaling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacologic inhibition of ERK activity. Conclusions: These data reveal an important contribution of IL11-related ERK activity for TGFβ-stimulated fibrosis phenotypes in HDFs and suggest IL11 as a potential therapeutic target in SSc.

2021-02-22 | GSE162966 | GEO

Therapeutic interference with mTorc1 restricts inflammation-associated and Stat3-dependent gastro-intestinal tumourigenesis in mice

Project description:Gp130 receptor engagement on neoplastic cells provides a link by which an inflammatory microenvironment facilitates tumour promotion. Although hyperactivation of the gp130-dependent Stat3 signalling node is commonly observed in solid tumours, Stat3 remains a challenging therapeutic target. To mimic excessive Stat3 signalling, we molecularly validate the gp130FF mouse as a preclinical model for inflammation-associated intestinal-type gastric cancer (IGC), with aberrant mammalian target of rapamycin (mTOR) pathway activity as shared feature. Accordingly, administration of the mTorc1 inhibitor RAD001 reversibly reduced IGC burden in gp130FF mice and suppressed colitis-associated cancer in wild-type mice. Since the therapeutic effect of RAD001 occurs independently of Stat3 hyperactivation, which is also dispensable for gp130-dependent engagement of the PI3K/Akt/mTorc1 pathway, we conclude that mTorc1 signalling limits tumour promoting Stat3 activity The mouse whole-genome gene expression profiling was performed on Illumina's MouseWG-6 v2.0 Expression BeadChips for 24 mice, with 8 mice in each group (gp130WT antral tissue, gp130FF unaffected antral tissue and gp130FF tumour tissue).

2013-01-29 | E-GEOD-35808 | biostudies-arrayexpress

LPS hypersensitivity of gp130 mutant mice is independent of elevated hematopoietic TLR4 signaling

Project description:The inflammatory mediator IL6 induced by LPS, which signals via TLR4, has been shown to feedback and augment TLR4 signaling when over-produced in LPS hypersensitive gp130F/F mice. The identity of the LPS/TLR4 responsive inflammatory signaling pathways and gene networks which are modulated by IL6 are unknown. Therefore, to understand the molecular consequences of gp130 hyperactivity in non-haemopoietic tissue on LPS-induced systemic inflammation, global gene expression profiling of livers was performed. The mouse 22K compugen oligo array from the Adelaide Microarray Facility was used to investigate the effect of LPS treatment on the livers of wildtype and gp130F/F mutant mice. Livers of both wildtype mice and gp130F/F mice at 6hr post LPS injection and also control livers wer collected. Each experimental group had 3 independant mice. In total 12 arrays were performed with a total of three biological replicates. A common reference design was used for this experiment. RNA extracted from eight pooled 17.5dpc C57BL/6 mouse embryos was used as the reference sample. 6 wildytpe mice and 6 gp130F/F mice were used in this study, with 3 mice of each genotype treated with LPS.

2011-05-17 | E-GEOD-29311 | biostudies-arrayexpress

Therapeutic interference with mTorc1 restricts inflammation-associated and Stat3-dependent gastro-intestinal tumourigenesis in mice

2013-01-29 | GSE35808 | GEO

LPS hypersensitivity of gp130 mutant mice is independent of elevated hematopoietic TLR4 signaling

2011-05-17 | GSE29311 | GEO

miRNA expression from gp130F/F mice antrum at 4 weeks of age

Project description:The molecular events promoting the initiation of gastric cancer (GC), the third most lethal cancer worldwide, are ill-defined. Here, we demonstrate that upregulation of miR-200 family members is associated with tumor initiation in the gp130F/F mouse model of early GC. The onset of gastric inflammation-associated adenomatous hyperplasia in gp130F/F mice occurs at ~6 weeks of age, with established intestinal-type tumors (3 months of age) progressively growing until a maximum size is reached at 6 months of age, with some evidence of carcinoma in situ. Since this phenotype histologically mimics early stage human GC, we therefore utilized gp130F/F mice as a model to identify miRNAs involved in the initiating molecular events leading to early stage GC. For this purpose, we performed miRNA microarrays on mouse gastric antrum tissue from gp130F/F and sex-matched littermate wild-type (gp130+/+) control mice aged 4 weeks; this age was chosen since antrum tissue from 4 week old (wo) gp130F/F mice is devoid of any histological signs of inflammation or hyperplasia, and is thus comparable to wild-type gastric antrum tissue

2017-12-01 | GSE93169 | GEO

Hepatic acute phase proteins control innate immune responses during infection by promoting myeloid derived suppressor cell function

Project description:Acute phase proteins (APPs) are an evolutionarily conserved family of proteins produced mainly in the liver in response to infection and inflammation. Despite vast pro- and anti-inflammatory properties ascribed to individual APPs, their collective function during infections remains poorly defined. Using a murine model for polymicrobial sepsis we show here that abrogation of APP production by hepatocyte-specific gp130 deletion, the signaling receptor shared by IL-6-family cytokines, dramatically increased mortality despite normal bacterial clearance. Hepatic gp130 signaling through signal transducer and activator of transcription (Stat)3 was required to control systemic inflammation. Notably, hepatic gp130/Stat3 activation was also a prerequisite to facilitate mobilization and tissue accumulation of myeloid-derived suppressor cells (MDSCs), a cell population mainly known for anti-inflammatory properties in cancer. We show that MDSCs were critical to regulate innate inflammation and their adoptive transfer efficiently protected gp130-deficient mice from sepsis-associated mortality. We identified serum amyloid A and Cxcl-1/KC as hepatic acute phase genes that cooperatively promoted MDSC mobilization, accumulation and survival. Administration of these proteins efficiently elevated MDSC numbers and reversed dysregulated inflammation and restored survival of gp130-deficient mice. Thus, gp130-dependent communication between the liver and MDSCs through acute phase proteins critically controls inflammatory responses during infection. Control [gp130f/f] and liver-specific Gp130 knockout [gp130delta(hepa)] mice were subjected to polymicrobial sepsis. Twelve hours after induction of sepsis mice were sacrificed and livers were removed. For control treatment mice were sacrified without any prior treatment. Total RNA was isolated and subjected to gene expression profiling.

2010-06-08 | E-GEOD-22009 | biostudies-arrayexpress

mRNA expression from wild type and gp130F/F mice antrum at 4 weeks of age in specific pathogen free (SPF) and germ free (GF) conditions

Project description:The role of microbe in promoting the initiation of gastric cancer (GC), the third most lethal cancer worldwide, are ill-defined. Here, we found that tumor size and weight in gp130F/F mouse stomach at condition were significantly reduced compared to those of at SPF condition. To investigate the underlying mechanism and how host genes were regulated in the presence/absence of microbe, arrays were performed in stomach tissue from gp130F/F and WT at 4 week old at SPF and GF conditions. The onset of gastric inflammation-associated adenomatous hyperplasia in gp130F/F mice occurs at ~6 weeks of age, with established intestinal-type tumors (3 months of age) progressively growing until a maximum size is reached at 6 months of age, with some evidence of carcinoma in situ. Since this phenotype histologically mimics early stage human GC, we therefore utilized gp130F/F mice as a model to identify miRNAs involved in the initiating molecular events leading to early stage GC. For this purpose, we performed miRNA microarrays on mouse gastric antrum tissue from gp130F/F and sex-matched littermate wild-type (gp130+/+) control mice aged 4 weeks; this age was chosen since antrum tissue from 4 week old (wo) gp130F/F mice is devoid of any histological signs of inflammation or hyperplasia, and is thus comparable to wild-type gastric antrum tissue.

2017-12-01 | GSE93173 | GEO

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