Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA105913 | ENA |
REPOSITORIES: ENA
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Project description:Inflammatory hepatocellular adenomas (IHCA) are benign liver tumours defined by the presence of inflammatory infiltrates and by the elevated expression of inflammatory proteins in tumour hepatocytes1,2. Here we show a striking activation of the IL6 signalling pathway in this tumour type, and sequencing candidate genes pinpointed this response to somatic gain-of-function mutations in the IL6ST gene that encodes the signalling co-receptor gp130. Indeed, ~70% of IHCA harbour small in-frame deletions that target the binding site of gp130 for IL6, and expression of the most frequent gp130 mutant, Delta-STVY190, in hepatocellular cells activates STAT3 in absence of ligand. Further, analysis of hepatocellular carcinomas revealed rare gp130 alterations always accompanied by ß-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant conversion of hepatocytes. The recurrent gain-of-function gp130 mutations in these human hepatocellular adenomas explains their inflammatory phenotype, and suggest that similar alterations may occur in other inflammatory epithelial tumours with STAT3 activation.
2008-12-24 | GSE11819 | GEO
Project description:Inflammatory hepatocellular adenomas (IHCA) are benign liver tumours defined by the presence of inflammatory infiltrates and by the elevated expression of inflammatory proteins in tumour hepatocytes1,2. Here we show a striking activation of the IL6 signalling pathway in this tumour type, and sequencing candidate genes pinpointed this response to somatic gain-of-function mutations in the IL6ST gene that encodes the signalling co-receptor gp130. Indeed, ~70% of IHCA harbour small in-frame deletions that target the binding site of gp130 for IL6, and expression of the most frequent gp130 mutant, Delta-STVY190, in hepatocellular cells activates STAT3 in absence of ligand. Further, analysis of hepatocellular carcinomas revealed rare gp130 alterations always accompanied by M-CM-^_-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant conversion of hepatocytes. The recurrent gain-of-function gp130 mutations in these human hepatocellular adenomas explains their inflammatory phenotype, and suggest that similar alterations may occur in other inflammatory epithelial tumours with STAT3 activation. HG-U133A Affymetrix GeneChipTM arrays were used to compare the expression profiles of 4 Inflammatory hepatocellular adenomas (IHCA) and 4 non related non-tumor livers. RNA labelling, hybridization and analysis were carried out following the manufacturerM-bM-^@M-^Ys instructions (Affymetrix, Santa Clara, CA). Raw data were obtained by using Microarray Suite 5.0 (MAS5) software, embedded in the Affymetrix GeneChip Operating Software (Santa Clara, USA); the resulting raw numerical data (CEL files) - available as supplementary files - collected from 8 Affymetrix GeneChips were pre-processed for normalization and filtering as described in [Rebouissou et al., J Biol Chem 2007, 282(19):14437-46, PMID: 17379603; Rebuissou et al., J Hepatol 2008, 49(1):61-71. PMID: 18466996 and Rebuissou et al., in preparation].
2008-12-24 | E-GEOD-11819 | biostudies-arrayexpress
Project description:Anti-proinflammatory cytokine therapies against interleukin (IL)-6 and tumor necrosis factor (TNF)-a are major advances in treating inflammatory diseases. We found that 2-deoxy-D-glucose (2-DG), a simple monosaccharide, attenuated IL-6 responses by inhibiting N-linked glycosylation of the IL-6 receptor gp130. Aglyco forms of gp130 failed to bind IL-6 and to activate downstream signals. 2-DG completely inhibited dextran sodium sulfate-induced inflammatory bowel disease that was partially dependent on IL-6.
2021-10-01 | GSE167598 | GEO
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
Project description:The protease BACE1 is a major drug target for Alzheimer’s disease, but chronic BACE1 inhibition is associated with non-progressive worsening that may be caused by modulation of unknown physiological BACE1 substrates. To identify in vivo-relevant BACE1 substrates we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as a new in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. In conclusion, BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans.
2023-02-23 | PXD035141 | Pride
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
2013-01-29 | GSE35808 | GEO
Project description:Background & Aims: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer usually developed in non-cirrhotic livers of children and young adults with unknown etiology. Treatment is limited to surgical intervention. To date, molecular pathogenesis of FLC has been poorly characterized. Herein, we aim to provide an integrative genomic analysis from a large series of FLC patients. Methods: A clinically annotated cohort of 77 FLCs was analyzed through wholetranscriptome, SNP-array and whole-exome sequencing. Non-negative matrix factorization was performed for class discovery, and GSEA, NTP, IPA and immunohistochemistry for functional annotation. GISTIC algorithm identified chromosomal aberrations; Mutect and VarScan2, somatic mutations, and Random survival forest the prognostic signature, validated in an independent cohort. Results: Unsupervised gene expression clustering revealed 3 robust molecular classes: Proliferation-51%, enriched with liver cancer proliferation signatures and mTOR signaling activation, Inflammation-26%, with pro-inflammatory cytokines signatures, and Unannotated-23%, with non-liver-related cancer signatures. Neuroendocrine genes and cholangiocyte and hepatocyte histological markers were present in all classes. FLC showed few copy number variations, being the most frequent: focal amplification at 8q24.3(12.5%), and deletions at 19p13(28%) and 22q13.32(25%). DNAJB1-PRKACA fusion transcript was observed in 79% of cases. FLC tumors had 32 damaging mutations on average, affecting uncommon genes in liver neoplasms (BRCA2, U2AF1). An 8-gene prognostic signature predicted survival in FLC patients. Conclusions: FLC genomic analysis reveals a unique molecular portrait characterized by uncommon damaging mutations and chromosomal aberrations, and a highly prevalent fusion protein. Three molecular classes, including Proliferation and Inflammation, define the biological behavior. Prognostic signature will allow better patient stratification. Gene-expression profiles of fresh frozen human fibrolamellar hepatocellular carcinoma
2015-02-12 | E-GEOD-57726 | biostudies-arrayexpress
Project description:Frequent occurrence of deletions in primary mediastinal B-cell lymphoma
| PRJNA100391 | ENA
Project description:Fibroblast growth factor 19 (FGF19) gene amplification is a common event in human hepatocellular carcinoma (HCC). The protein it encodes acts as a hormone with multiple metabolic functions beneficial for the liver, which has led to the development of analogues for the treatment of metabolic disorders such as Nonalcoholic Steatohepatitis (NASH). The most studied analogue is Aldafermin (NGM282), with previous reports showing the absence of oncogenic properties when given alone. However, potential oncogenic cooperation with frequent disrupted pathways in HCC have not been studied. Here, we used hydrodynamic gene transfer and recombinant protein injection to study oncogenic cooperation between FGF19 and its rodent orthologue FGF15, FGF19 analogue Aldafermin and common HCC events. We found a strong cooperation between FGF15/19 or Aldafermin and hepatocyte overexpression of Myc. The resulting tumours appeared in a short frame (2 to 4 weeks), were well differentiated, and expressed typical HCC markers (alpha foetoprotein and glypican 3). Transcriptomic and pathological analyses showed that Myc/FGF19 and Myc/Aldafermin tumours were almost identical. Our findings could be clinically relevant since clinical studies are currently ongoing in patients with cirrhosis, a condition associated with high susceptibility to HCC development.
2023-12-18 | GSE242953 | GEO
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