Multi-omics analysis of mutant and wild-type β-catenin networks
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE95670 | GEO | 2018/07/17
REPOSITORIES: GEO
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Project description:We used interaction and expression proteomic techniques in conjunction with RNA-Seq transcriptomic analysis to analyse how a β-catenin stabilizing mutation alters molecular networks in colorectal cancer cells. Integrated computational analyses of allowed us to identify significantly altered sub-networks linked to β-catenin oncogenesis.
2018-05-18 | PXD006053 | Pride
Project description:Medulloblastoma is the most frequent malignant pediatric brain tumor. Considerable efforts are dedicated to identify markers that help to refine treatment strategies. The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favorable patient outcome. We report a series of 72 pediatric medulloblastomas evaluated for beta-catenin immunostaining, CTNNB1 mutations, and studied by comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-catenin showed extensive nuclear staining (>50% of the tumor cells) in 6 cases and focal nuclear staining (<10% of cells) in 3 cases. The other cases exhibited either a signal strictly limited to the cytoplasm (58 cases) or were negative (5 cases). CTNNB1 mutations were detected in all beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented a strong activation of the Wnt/beta-catenin pathway. Remarkably, 5 out of these 6 tumors showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumors with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5-121.2) from diagnosis. All three patients with a focal nuclear staining of beta-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumors represent a distinct molecular subgroup of medulloblastomas with favorable outcome, indicating that therapy de-escalation should be considered. Yet, international consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved. A series of 72 pediatric medulloblastoma tumors has been studied at the genomic level (array-CGH), screened for CTNNB1 mutations and beta-catenin expression (immunohistochemistry). A subset of 40 tumor samples has been analyzed at the RNA expression level (Affymetrix HG U133 Plus 2.0). Correlations between the genomic data, the expression data, the mutational screening, the pathological classification and clinical data is presented in the study. note: aCGH data not submitted to GEO
2009-02-02 | E-GEOD-12992 | biostudies-arrayexpress
Project description:Oncogenic stabilizing mutations in the beta-catenin gene CTNNB1 are common in one class of human Wilms tumors. To model these tumors, we crossed mice carrying an inducible Cre recombinase (Rosa26-CreERT2) with a conditional gain-of-function beta-catenin allele (Ctnnb1Ex3flox). We obtained kidneys at embryonic day 13.5 and placed them in organ culture with tamoxifen. Multiple small tumors formed in the Ctnnb1∆Ex3 kidneys while the control kidneys developed normally. Immunostaining for Sall1, a marker of condensing metanephric mesenchyme, indicated that the tumors arise from this tissue compartment, analogous to the origin of human Wilms tumors. Expression profiling identified a set of induced genes overlapping with those up-regulated in human Wilms tumors with CTNNB1 mutations, including genes encoding feedback inhibitors of Wnt/beta-catenin signaling, the epithelial-mesenchymal transition (EMT) inducers, and the transcription factor E2-2 (ITF2/TCF4). A conditional deletion of E2-2 showed that this gene is important for growth of the nephroblastomas, in part via promoting an epithelial to mesenchymal transition downstream of beta-catenin. Given these cross-species validations, and genetic proof of the oncogenic function of a key downstream target gene, we expect that this rapid and efficient organ culture model will be useful for further studies to dissect and inhibit oncogenic Wnt/beta-catenin signaling.
2017-02-20 | GSE63418 | GEO
Project description:Purpose: WNT signaling activation in colorectal cancers (CRCs) occurs mainly through APC inactivation or, more uncommonly, β-catenin activation. Both processes promote β-catenin nuclear accumulation, which transcriptionally up-regulates epithelial-to-mesenchymal transition (EMT)-related genes. Experimental Design: We investigated β-catenin localization, downstream gene expression, and phenotypic alterations in HCT116 cells containing a wild-type (HCT116-WT) or mutant β-catenin allele (HCT116-MT), or parental cells with both WT and mutant alleles (HCT116-P). We then analyzed β-catenin localization and associated phenotypes in CRC tissues. Results: Wild-type β-catenin mainly localized at the cell membrane, whereas mutant showed predominantly nuclear localization; membranous, cytoplasmic, and nuclear localization was observed in HCT116-P cells. Microarray analysis revealed significant down-regulation of Claudin-7 and E-cadherin in HCT116-MT vs. HCT116-WT cells. Claudin-7 was also down-regulated in HCT116-P vs. HCT116-WT cells, although E-cadherin expression was unaffected. Altered expression of cell-cell junction-related molecules led to tight junction (TJ) impairment in HCT116-P, and dual loss of TJs and adherens junctions (AJs) in HCT116-MT. TJ loss increased migration and invasion activities of HCT116-WT, whereas AJ loss was required to further up-regulate these activities in HCT116-P. Immunohistochemistry analysis of 101 stage III CRC tissues revealed high nuclear β-catenin expression (≥30% of tumor cells) in 15 (14.9%) samples, low nuclear expression (1-29%) in 53 (52.5%) samples, and undetectable nuclear expression in 33 (32.6%) samples, with a trend toward more frequent down-regulation of Claudin-7 and E-cadherin, and increased metastasis in CRCs with high vs. low nuclear β-catenin. Conclusions: β-catenin activation and nuclear translocation induce EMT progression by modifying cell-cell junctions, and are associated with aggressive behaviors of CRCs.
2019-11-18 | GSE126845 | GEO
Project description:Oncogenic stabilizing mutations in the beta-catenin gene CTNNB1 are common in one class of human Wilms tumors. To model these tumors, we crossed mice carrying an inducible Cre recombinase (Rosa26-CreERT2) with a conditional gain-of-function beta-catenin allele (Ctnnb1Ex3flox). We obtained kidneys at embryonic day 13.5 and placed them in organ culture with tamoxifen. Multiple small tumors formed in the Ctnnb1∆Ex3 kidneys while the control kidneys developed normally. Immunostaining for Sall1, a marker of condensing metanephric mesenchyme, indicated that the tumors arise from this tissue compartment, analogous to the origin of human Wilms tumors. Expression profiling identified a set of induced genes overlapping with those up-regulated in human Wilms tumors with CTNNB1 mutations, including genes encoding feedback inhibitors of Wnt/beta-catenin signaling, the epithelial-mesenchymal transition (EMT) inducers, and the transcription factor E2-2 (ITF2/TCF4). A conditional deletion of E2-2 showed that this gene is important for growth of the nephroblastomas, in part via promoting an epithelial to mesenchymal transition downstream of beta-catenin. Given these cross-species validations, and genetic proof of the oncogenic function of a key downstream target gene, we expect that this rapid and efficient organ culture model will be useful for further studies to dissect and inhibit oncogenic Wnt/beta-catenin signaling.
2017-02-20 | GSE63415 | GEO
Project description:Wnt/β-catenin signaling is active during cellular quiescence in muscle myoblasts. Exposure of quiescent myoblasts to Wnt3a led to deregulation of genes associated with both myogenic differentiation and proliferation. Genome-wide analysis Ctnnb1 by ChIP-chip revealed quiescence-specific enrichment on genes of multiple functional classes. The major class of genes bound by Ctnnb1were Wnt pathway genes and all occupied promoters were highly enriched for TCF DNA binding motifs. Cross-comparison of ChIP-Chip with transcriptome data revealed both transcriptional activation as well as repression in Ctnnb1 occupied genes. Inhibition of Ctnnb1-mediated transactivation using shRNA and pharmacological agents led to de-regulation of the quiescence-associated transcriptional profile. Ctnnb1 binding is associated with repression of myogenic genes and cell cycle progression factors while maintaining differential response by these genes to Wnt signaling during quiescence. Microarray analysis of Wnt3A treated G0 myoblasts compared to untreated G0 cells
2020-03-31 | GSE141506 | GEO
Project description:Medulloblastoma is the most frequent malignant pediatric brain tumor. Considerable efforts are dedicated to identify markers that help to refine treatment strategies. The activation of the Wnt/beta-catenin pathway occurs in 10-15% of medulloblastomas and has been recently described as a marker for favorable patient outcome. We report a series of 72 pediatric medulloblastomas evaluated for beta-catenin immunostaining, CTNNB1 mutations, and studied by comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-catenin showed extensive nuclear staining (>50% of the tumor cells) in 6 cases and focal nuclear staining (<10% of cells) in 3 cases. The other cases exhibited either a signal strictly limited to the cytoplasm (58 cases) or were negative (5 cases). CTNNB1 mutations were detected in all beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented a strong activation of the Wnt/beta-catenin pathway. Remarkably, 5 out of these 6 tumors showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumors with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow-up of 75.7 months (range 27.5-121.2) from diagnosis. All three patients with a focal nuclear staining of beta-catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1-mutated tumors represent a distinct molecular subgroup of medulloblastomas with favorable outcome, indicating that therapy de-escalation should be considered. Yet, international consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved.
2009-02-02 | GSE12992 | GEO
Project description:Endothelial-derived Wnt/Ctnnb1-signaling is an important angiocrine regulator. Ctnnb1 gain-of-function (GOF) in liver sinusoidal endothelial cells was generated by crossing Clec4g-iCre (Wohlfeil SA et al, 2019, Cancer Research) with Ctnnb1(Ex3) fl/fl mice (Harada N et al, 1999, EMBO J) to analyze the effects of endothelial β-catenin signaling on LSEC differentiation and liver function We used microarrays to detail the global programme of gene expression in liver sinusoidal endothelial cells with β-catenin (Ctnnb1) gain-of-function compared to control animals.
2021-11-18 | GSE175777 | GEO
Project description:Mutations of β-catenin gene (CTNNB1) are frequent in adrenocortical adenomas (AA) and carcinomas (ACC). However, the target genes of CTNNB1 have not yet been identified in adrenocortical tumors. Our objective was to identify genes de-regulated in adrenocortical tumors harbouring CTNNB1 genetic alterations. We compared gene expression profiles of AA with (n: 3) and without (n: 4) CTNNB1 mutations using Affymetrix arrays.
2011-04-09 | E-GEOD-28476 | biostudies-arrayexpress
Project description:Deregulation of the canonical Wnt/beta-catenin pathway is one of the earliest events in the pathogenesis of colon cancer. Mutations in APC or CTNNB1 are frequent in colon cancer and cause aberrant stabilization of beta-catenin, which activates Wnt target genes by binding to chromatin via TCF/LEF transcription factors. In a comprehensive study, we conducted an integrative analysis of genome-wide chromatin occupancy of beta-catenin by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) along with gene expression profiling changes resulting from RNAi-mediated knockdown of beta-catenin in colon cancer cells. This experiment series represents the gene expression changes detected by microarray as a result of CTNNB1 perturbation. SW480 cells were transfected with control and beta-catenin siRNAs. Twenty-four hours after transfection, RNA was extracted from the cells using the RNeasy kit (Qiagen, Valencia, CA) and genome-wide cDNA microarray expression analysis was performed. The data reported here are the microarray data as processed by the standard Rosetta Resolver(R) ratio method for Agilent microarrays.
2013-12-27 | E-GEOD-53656 | biostudies-arrayexpress