Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA383109 | ENA |
REPOSITORIES: ENA
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Project description:Ovarian cancer is a nearly uniform lethal disease and its highly aggressive metastatic phenotype portends a poor prognosis. Lack of a well-controlled, relevant experimental model has been a major obstacle to identifying key molecules causing metastasis. Here we describe the creation of a new isogenic model of spontaneous human ovarian cancer metastasis exhibiting opposite phenotypes - highly metastatic (HM) and non-metastatic (NM) - both in vitro and in vivo. HM was unique in its ability to metastasize consistently to the peritoneum, mimicking the major dissemination route of human ovarian cancer. In contrast, NM failed to form detectable metastases although it was equally tumorigenic. Using comparative label-free quantitative LC-MS/MS, we identified b-catenin which we demonstrated for the first time a direct role in the pathogenesis of ovarian cancer metastasis. Our studies also revealed a previously unrecognized role of b-catenin in the downregulation of multiple microRNAs (miRNAs) through attenuating miRNA biogenesis by targeting Dicer, a key component of the microRNA processing machinery. One such downregulated miRNAs was miR-29s involved in epithelial-to-mesenchymal transition and subsequent stem cell traits. Silencing b-catenin or overexpressing Dicer or miR-29 mimics in HM significantly reduced the ability of these cells to migrate. B-catenin knockdown cells also failed to metastasize in an orthotopic model of ovarian cancer. Meta-analysis revealed an increase in CTNNB1 and a decrease in DICER1 expression levels in the high-risk group. These results uncover b-catenin as a critical player in promoting ovarian cancer aggressiveness and a new mechanism linking between b-catenin and miRNA downregulation underlying this process.
2017-07-03 | PXD006327 | Pride
Project description:Deregulation of canonical Wnt/beta-catenin pathway is one of the earliest events in the pathogenesis of colon cancer. Mutations in APC or CTNNB1 (beta-catenin gene) are highly frequent in colon cancer and cause aberrant stabilization of b-catenin, which activates the transcription of Wnt target genes by binding to chromatin via the TCF/LEF transcription factors. Here we report an integrative analysis of genome-wide chromatin occupancy of b-catenin by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) and gene expression profiling by microarray analysis upon RNAi-mediated knockdown of beta-catenin in colon cancer cells (GSE53656). Immunoprecipitated samples from human colon cancer SW480 cells with antibodies against beta-catenin and control IgG respectively were used for ChIP-seq experiments.
2014-03-12 | E-GEOD-53927 | biostudies-arrayexpress
Project description:Deregulation of canonical Wnt/beta-catenin pathway is one of the earliest events in the pathogenesis of colon cancer. Mutations in APC or CTNNB1 (beta-catenin gene) are highly frequent in colon cancer and cause aberrant stabilization of b-catenin, which activates the transcription of Wnt target genes by binding to chromatin via the TCF/LEF transcription factors. Here we report an integrative analysis of genome-wide chromatin occupancy of b-catenin by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) and gene expression profiling by microarray analysis upon RNAi-mediated knockdown of beta-catenin in colon cancer cells (GSE53656).
2014-03-12 | GSE53927 | GEO
Project description:Spheroids are 3D multi-cell aggregates formed in non-addherent culture conditions. In ovarian cancer (OC), they serve as a vehicle for cancer cell dissemination in the peritoneal cavity. We investigated genes and networks upregulated in three dimensional (3D) versus two-dimensional (2D) culture conditions by Affymetrix gene expression profiling and identified ALDH1A1, a cancer stem cell marker as being upregulated in OC spheroids. Network analysis confirmed ALDH1A1 upregulation in spheroids in direct connection with elements of the beta-catenin pathway. A parallel increase in the expression levels of beta-catenin and ALDH1A1 was demonstrated in spheroids vs. monolayers an in successive spheroid generations by using OC cell liness and primary OC cells. The percentage of Aldefluor positive cells was significantly higher in spheroids vs. monolayers in IGROV1, A2780, SKOV3, and primary OC cells. B-catenin knock-down decreased ALDH1A1 expression and chromatin immunoprecipitation demonstrated that beta-catenin directly binds to the ALDH1A1 promoter. Both siRNA mediated beta-catenin knock-down and a novel ALDH1A1 small molecule enzymatic inhibitor described here for the first time, decreased the number of OC spheroids (p<0.001) and cell viability. These data strongly support the role of beta-catenin regulated ALDH1A1 in the maintenance of OC spheroids and of a stem cell phenotype and propose new ALDH1A1 inhibitors targeting this cell population. Different gene profiles were observed in ovarian cancer spheroids versus ovarian cancer monolayers. Nine samples were analyzed in triplicate. Each group is a reference.
2014-01-03 | E-GEOD-53759 | biostudies-arrayexpress
Project description:To elucidate the comprehensive changes regulated by β-catenin/TCF-dependent signaling in liver cancer cells, we explored a global gene expression of HepG2 cells after knockdown of β-catenin.
2017-09-01 | GSE94858 | GEO
Project description:Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective new approach to treating prostate cancer. Here we provide proof-of-concept that a small molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/TCF and β-catenin/AR protein interaction, reflecting the fact that TCF and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and β-catenin cofactor, CARM1, providing new insight into the unrecognized function of β-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model, and blocked renewal of bicalutamide-resistant sphere forming cells, indicating the therapeutic potential of this approach. Compare and contrast the expression profile of prostate cancer cells treated with a Wnt inhibitor (C3) with respect to β-catenin and AR knockdown (all samples in duplicates).
2014-01-23 | E-GEOD-49295 | biostudies-arrayexpress
Project description:During mesenchymal stem cell (MSC) differentiation, both Wnt signaling and the development of a rigid cytoskeleton promote commitment to the osteoblastic over adipogenic lineage. β-catenin is thought to play a critical role in Wnt effects. We show that β-catenin was additive with cytoskeletal signals to prevent adipogenesis, and β-catenin knockdown promoted adipogenesis even when the actin cytoskeleton was depolymerized. β-catenin also prevented osteoblast commitment in a cytoskeletal-independent manner, with β-catenin knockdown enhancing lineage commitment. Chip-seq showed that β-catenin associated with the promoter of EZH2, a key component of the PRC2 complex that governs genome methylation. Knocking down β-catenin lowered EZH2 levels and H3K27me3 at osteogenic loci. Further, when EZH2 was inhibited, β-catenin ’s anti-differentiation effects were lost. These results indicate that regulating EZH2 activity is key to β-catenin effects on MSC to preserve MSC multipotentiality.
2019-10-17 | GSE138980 | GEO
Project description:The tetraspanin CD63 is implicated in pro-metastatic signaling pathways, but so far, it is unclear how CD63 levels affect the tumor cell phenotype. Here, we investigated the effect of CD63 modulation in different metastatic tumor cell lines. In vitro, knock down of CD63 induced a more epithelial-like phenotype concomitant with increased E-cadherin expression, downregulation of its repressors Slug and Zeb1, and decreased N-cadherin. In addition, β-catenin protein was markedly reduced, negatively affecting expression of the target genes MMP-2 and PAI-1. β-catenin inhibitors mimicked the epithelial phenotype induced by CD63 knock down. Inhibition of β-catenin upstream regulators PI3K/AKT or GSK3β could rescue the mesenchymal phenotype underlining the importance of the β-catenin pathway in CD63-regulated cell plasticity. CD63 knock down-induced phenotypical changes correlated with a decrease of experimental metastasis, while CD63 overexpression enhanced the tumor cell-intrinsic metastatic potential. Taken together, our data show that CD63 is a crucial player in the regulation of the tumor cell-intrinsic metastatic potential by affecting cell plasticity. Stable knock down of CD63 was performed in SKOV3ipL ovarian carcinoma cell line using 2 shRNAs lentiviral constructs (sh49 and sh51), and as a negative control, a shNT construct. Parental cells, control shNT and the 2 shCD63 cell lines were seeded 24 hours prior to RNA isolation on a 10 cm dish, labelling and hybridization on microarrays. One color experiment with 2 biological replicates of the 4 experimental conditions: SKOV3ipL, SKOV3ipL_shNT, SKOV3ipL_sh49 and SKOV3ipL_sh51.
2015-01-23 | E-GEOD-61957 | biostudies-arrayexpress
Project description:MicroRNAome of highly metastatic and non-metastatic human breast cell lines
| PRJNA119063 | ENA
Project description:Unrestrained transcriptional activity of β-CATENIN and its binding partner TCF7L2 frequently underlies colorectal tumor initiation and is considered an obligatory oncogenic driver throughout intestinal carcinogenesis. Yet, the TCF7L2 gene carries inactivating mutations in about 10 % of colorectal tumors and is non-essential in colorectal cancer (CRC) cell lines. To determine whether CRC cells acquire TCF7L2-independence through cancer-specific compensation by other T-cell factor (TCF)/lymphoid enhancer‑binding factor (LEF) family members, or rather lose addiction to β-CATENIN/TCF7L2-driven gene expression altogether, we generated multiple CRC cell lines entirely negative for TCF/LEF or β-CATENIN expression. Viability of these cells demonstrates complete β‑CATENIN- and TCF/LEF-independence, albeit one β-CATENIN-deficient cell line eventually became senescent. Absence of TCF/LEF proteins and β-CATENIN consistently impaired CRC cell proliferation, reminiscent of mitogenic effects of WNT/β-CATENIN signaling in the healthy intestine. Despite this common phenotype, β-CATENIN-deficient cells exhibited highly cell-line-specific gene expression changes with little overlap between β-CATENIN- and TCF7L2-dependent transcriptomes. Apparently, β‑CATENIN and TCF7L2 control sizeable fractions of their target genes independently from each other. The observed divergence of β-CATENIN and TCF7L2 transcriptional programs, and the finding that neither β-CATENIN nor TCF/LEF activity is strictly required for CRC cell survival has important implications when evaluating these factors as potential drug targets.
2022-12-13 | GSE199835 | GEO