β-catenin activation down-regulates cell-cell junction-related genes and induces epithelial-to-mesenchymal transition in colorectal cancers
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ABSTRACT:
PROVIDER: PRJNA523503 | ENA |
REPOSITORIES: ENA
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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:WNT signaling activation in colorectal cancers (CRCs) occurs through APC inactivation or β-catenin mutations. Both processes promote β-catenin nuclear accumulation, which up-regulates epithelial-to-mesenchymal transition (EMT). We investigated β-catenin localization, transcriptome, and phenotypic differences of 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 expression and associated phenotypes in CRC tissues. Wild-type β-catenin showed membranous localization, whereas mutant showed nuclear localization; both nuclear and non-nuclear localization were observed in HCT116-P. Microarray analysis revealed down-regulation of Claudin-7 and E-cadherin in HCT116-MT vs. HCT116-WT. Claudin-7 was also down-regulated in HCT116-P vs. HCT116-WT without E-cadherin dysregulation. We found that ZEB1 is a critical EMT factor for mutant β-catenin-mediated loss of E-cadherin and Claudin-7 in HCT116-P and HCT116-MT cells. We also demonstrated that E-cadherin binds to both WT and mutant β-catenin, and loss of E-cadherin releases β-catenin from the cell membrane and leads to its degradation. Alteration of Claudin-7, as well as both Claudin-7 and E-cadherin respectively caused tight junction (TJ) impairment in HCT116-P, and dual loss of TJs and adherens junctions (AJs) in HCT116-MT. TJ loss increased cell motility, and subsequent AJ loss further up-regulated that. Immunohistochemistry analysis of 101 CRCs revealed high (14.9%), low (52.5%), and undetectable (32.6%) β-catenin nuclear expression, and high β-catenin nuclear expression was significantly correlated with overall survival of CRC patients (P = 0.009). Our findings suggest that β-catenin activation induces EMT progression by modifying cell-cell junctions, and thereby contributes to CRC aggressiveness.
| S-EPMC6895046 | biostudies-literature
Project description:The BCR-ABL1 translocation product is the cause of Chronic Myeloid Leukemia (CML) and of a significant fraction of adult-onset B-Acute Lymphoblastic Leukemia (B-ALL) cases. Here we identify an essential role for gamma-catenin (junction plakoglobin) in B lineage restricted cells for the progression of B-ALL in a mouse model. The array analysis of preleukemic B cells aimed at identifying genes that explain the deficient B-ALL progression in the absence gamma-catenin. Total bone marrow cells from chimeric mice expressing or lacking gamma-catenin in the hematopoietic compartment were transduced with BCR-ABL1+ IRES GFP retrovirus before transplantation into lethally irradiated wild type recipients. Three weeks later, GFP+ (BCR-ABL1+) B220+ BP-1+ B cells were flow sorted from the bone marrow of preleukemic recipient mice. The analysis includes 3 replicates for gamma-catenin WT and 3 replicates for gamma-catenin KO BCR-ABL1+ BP1+ B cells.
2014-02-08 | E-GEOD-54793 | biostudies-arrayexpress
Project description:Aberrant expression of adherens junction (AJ) proteins is frequently observed in human cancers. However, how these factors contribute to tumorigenesis is poorly understood and for some factors such as α‐catenin contradicting data has been described. Systematic analysis of TCGA expression data derived from 23 human tumor types revealed that α‐catenin was significantly reduced in some malignancies (e.g., colon adenocarcinoma), while elevated α‐catenin expression in other entities was associated with poor clinical outcome (e.g., hepatocellular carcinoma; HCC). In HCC cells, α‐catenin was detectable at the membrane as well as cytoplasm where it supported tumor cell proliferation and migration. Additionally, in vivo experiments illustrated moderate oncogenic potential of α‐catenin. To identify functionally relevant binding partners of α‐catenin, BioID combined with mass spectrometry was performed. This led to the identification of cytokinesis regulator centrosomal protein 55 (CEP55) as novel α‐catenin interacting protein in the cytoplasm that was stabilized by α‐catenin. Interestingly, CEP55 was highly expressed in human HCC tissues and its overexpression was transcriptionally controlled by a complex consisting of TEA domain transcription factors (TEADs), forkhead box M1 (FoxM1), and yes-associated protein (YAP). Surprisingly, CEP55 did not significantly affect HCC cell proliferation but supported migration in conjunction with α‐catenin. Together, the enrichment of pro-migratory CEP55 in HCC cells is mediated by two mechanisms: transcriptional activation via the FoxM1/TEAD/YAP as well as the cytoplasmic stabilization through interaction with the AJ protein α‐catenin.
2023-07-20 | PXD039222 | Pride
Project description:In nucleated cells, β-catenin, the key downstream effector of this pathway, is a dual function protein, regulating the coordination of gene transcription and cell–cell adhesion. The specific role of β-catenin in the anucleate platelet however remains elusive. Here, we performed a label-free quantitative proteomic analysis of β-catenin immunoprecipitates from human platelets identifying 9 co-immunoprecipitating proteins. GO biological pathway analysis revealed a significant enrichment of specific functional terms including 'cell adhesion', 'cell junction organization' and ‘adherens junction organization'. Our bioinformatics data suggests that human platelet β-catenin may be involved in facilitating cell adhesion and cell junctions. We found three proteins co-immunoprecipitating with β-catenin under both resting and activated conditions, four proteins under resting condition only and two proteins under activated condition only.
2018-07-05 | PXD008130 | Pride
Project description:The BCR-ABL1 translocation product is the cause of Chronic Myeloid Leukemia (CML) and of a significant fraction of adult-onset B-Acute Lymphoblastic Leukemia (B-ALL) cases. Here we identify an essential role for gamma-catenin (junction plakoglobin) in B lineage restricted cells for the progression of B-ALL in a mouse model. The array analysis of preleukemic B cells aimed at identifying genes that explain the deficient B-ALL progression in the absence gamma-catenin. Total bone marrow cells from chimeric mice expressing or lacking gamma-catenin in the hematopoietic compartment were transduced with BCR-ABL1+ IRES GFP retrovirus before transplantation into lethally irradiated wild type recipients. Three weeks later, GFP+ (BCR-ABL1+) B220+ BP-1+ B cells were flow sorted from the bone marrow of preleukemic recipient mice.
2014-02-08 | GSE54793 | GEO
Project description:mRNASeq on Cre-loxP-engineered mouse liver primary cancers with beta-catenin activation
| PRJEB44400 | ENA
Project description:Data associated with the manuscript "Top-Down Individual Ion Mass Spectrometry Reveals 85-110 kDa Catenin Phospho-Proteoforms Regulated by Actomyosin Contractility"
2025-07-30 | MSV000098690 | MassIVE
Project description:CTNNB1 exon 3 mutation is a well-established driver of nearly 30% of endometrioid endometrial cancers (EEC), and this is associated with worse patient survival. The purpose of this study was to determine downstream gene expression in these cancers with nuclear or membrane/cytoplasmic mutant b-catenin protein localization. We determined that EECs with exon 3 CTNNB1 mutations have variable b-catenin localization, and this is associated with profoundly distinct foci of gene expression within the same cancer.
2025-05-12 | GSE278479 | GEO
Project description:ß-catenin is a main oncogene in a large number of cancers (colorectal, liver, melanoma, uterus). Local immunosuppression induced by certain cancers remains a major problem of resistance to immunotherapies and its molecular mechanism remains poorly understood. Recently, ß-catenin mutated tumors (hepatocellular carcinoma (HCC) and melanoma) have been described as promoting immune evasion and resistance to anti-PD1 immunotherapy. Based on preliminary data obtained in HCC, we hypothesize that a defect in intercellular communication could be the cause of this immune evasion. The main objective of this project is to identify proteomic signatures of factors that can induce this immune escape in ß-catenin mutated HCC such as exosomes.
2024-07-08 | PXD043841 | Pride