Activation of beta-catenin in hepatocellular carcinoma (mouse Ctnnb1 knockout)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE43628 | GEO | 2014/12/31
SECONDARY ACCESSION(S): PRJNA186854
REPOSITORIES: GEO
Similar Datasets
Project description:CTNNB1 is the most frequently mutated gene in hepatocellular carcinoma (HCC). However, its clinical relevance remains controversial. We determined an evolutionarily conserved β-catenin signature by comparative analysis of gene expression data from human HCC and a mouse model (GSE43628). We generated gene expression data from the tumors of 88 HCC patients who underwent surgical resection as the primary treatment. We used these gene expression data to develop a new prognostification model for prognosis of HCC after surgery. We generated gene expression data from the tumors of 88 HCC patients who underwent surgical resection as the primary treatment.
2015-05-21 | E-GEOD-43619 | biostudies-arrayexpress
Project description:CTNNB1 is the most frequently mutated gene in hepatocellular carcinoma (HCC). However, its clinical relevance remains controversial. We determined an evolutionarily conserved β-catenin signature by comparative analysis of gene expression data from human HCC and a mouse model (GSE43628). We generated gene expression data from the tumors of 88 HCC patients who underwent surgical resection as the primary treatment. We used these gene expression data to develop a new prognostification model for prognosis of HCC after surgery.
2015-05-21 | GSE43619 | GEO
Project description:Background & Aims: Patients with beta-catenin (encoded by CTNNB1)-mutated hepatocellular carcinoma (HCC) have demonstrated limited clinical benefit to first-line immunotherapy (IO). Animal models of HCC expressing mutant-beta-catenin and additional aberrations via hydrodynamic tail vein injection with sleeping beauty transposon/transposase (SB-HDTVI) represent clinically relevant human HCC subsets. Here, we perform transcriptomic analysis on multiple beta-catenin-mutated and non-mutated HCC animal models to identify Mutated beta-catenin Gene Signature (MBGS) for HCC patient stratification for CTNNB1-mutations and IO response. Methods: We co-expressed in mice mutant-NFE2L2 and hMET +- mutant-CTNNB1 via SB-HDTVI and monitored for HCC development. Bulk RNA-sequencing was assessed for transcriptional differences between various beta-catenin-mutated and non-mutated models. MBGS was generated for predictive ability of CTNNB1 mutations and IO resistance in multiple HCC patient cohorts. Results: Co-expression of S45Y-beta-catenin + G31A-NFE2L2 + hMet (beta-N-M) resulted in HCC development by 4.5 weeks while co-expression of G31A-NFE2L2 + hMet (N-M) led to HCC by 14 weeks with tumors being positive for expected targets by immunohistochemistry (IHC). Bulk RNA-sequencing comparing beta-catenin-driven versus non-beta-catenin driven models yielded 95 common upregulated genes. Differential gene expression analysis of the common genes comparing CTNNB1-mutated vs non-mutated TCGA patients narrowed the gene panel to 13-(or 10-) genes. This MBGS predicted CTNNB1-mutation status in TCGA (n=374) and French (n=398) patient cohorts (with ROC AUC of 0.90 and 0.94). High MBGS expression was also associated with no overall and progression-free survival benefit when comparing atezolizumab + bevacizumab versus sorafenib arms in IMbrave150 cohort implying fewer treatment effects. Conclusions: In an era of patient molecular stratification for HCC, MBGS may aid in optimally selecting patients for IO through diagnosis of a molecular subset which lacks optimal response.
2024-10-09 | GSE261316 | GEO
Project description:Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. β-catenin has dual cellular functions as a component of the Wnt signaling pathway and adherens junctions. HCC-associated CTNNB1 mutations stabilize the β-catenin protein, leading to nuclear and/or cytoplasmic localization of β-catenin and downstream activation of Wnt target genes. In patient HCC samples, β-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in β-catenin activation are not well understood. To define mechanisms of β-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated β-catenin in 1) a small number of hepatocytes in early development; or 2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated β-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/β-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish β-catenin-driven HCC. Ingenuity Pathway Analysis of differentially expressed genes in the Cre-lox HCC model revealed that “Cancer” and “Liver Tumor” categories were significantly altered, indicating transcriptional similarities with human HCC and other vertebrate HCC models. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish β-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca, and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous β-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.
2019-09-27 | GSE137787 | GEO
Project description:Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. β-catenin has dual cellular functions as a component of the Wnt signaling pathway and adherens junctions. HCC-associated CTNNB1 mutations stabilize the β-catenin protein, leading to nuclear and/or cytoplasmic localization of β-catenin and downstream activation of Wnt target genes. In patient HCC samples, β-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in β-catenin activation are not well understood. To define mechanisms of β-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated β-catenin in 1) a small number of hepatocytes in early development; or 2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated β-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/β-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish β-catenin-driven HCC. Ingenuity Pathway Analysis of differentially expressed genes in the Cre-lox HCC model revealed that “Cancer” and “Liver Tumor” categories were significantly altered, indicating transcriptional similarities with human HCC and other vertebrate HCC models. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish β-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca, and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous β-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.
2019-09-27 | GSE137784 | GEO
Project description:Metastasis is a major obstacle to better prognosis in patients with hepatocellular carcinoma (HCC). Mesenchymal-epithelial transition (MET) is the driving force for metastatic colonization in which E-cadherin reexpression is a critical procedure. It has been reported that the loss of paired-related homeobox transcription factor 1 (PRRX1) is required for cancer cell metastasis in vivo. However, the role of PRRX1 in MET and how its downregulation triggers E-cadherin reexpression are unknown. In this study, we performed a systematic, mechanistic study regarding the role of PRRX1 in MET of HCC. We observed PRRX1 downregulation in HCC tissues which correlated with early metastasis and short overall survival time. Overexpression of PRRX1 induced EMT, but did not promote metastasis formation, while knockdown of PRRX1 promoted metastasis and colonization of circulating HCC cells as shown in in situ liver tumor model and colonization model. PRRX1 protein levels reversely correlated with E-cadherin levels in HCC cell lines. PRRX1 knockdown promoted E-cadherin reexpression and cell proliferation, inhibited cell invasion and migration. The microarray results showed that PRRX1 deficiency regulated extracellular matrix (ECM) interaction, focal adhesion, TGF-β signaling and cancer pathways. PRRX1 knockdown upregulated PITX2 (paired like homeodomain 2) and inhibited CTNNB1 (catenin beta 1) and SLUG. Silencing of PITX2 reversed CTNNB1 and SLUG inhibition and E-cadherin reexpression. PITX2 upregulation increased miR-200a and miR-200b/429, which further inhibited the transcription of CTNNB1 and SLUG, respectively, thus abrogating the inhibitory effect on E-cadherin. In conclusion, our data showed that the downregulation of PRRX1 induced E-cadherin reexpression through PITX2/miR-200a/CTNNB1 and PITX2/miR-200b/429/SLUG pathway, making PRRX1 a novel prognostic factor for HCC.
2020-04-18 | GSE148851 | 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: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:We report transcritomic characterization of changes in CTNNB1 mutation positive HCCs in comparison to paratumoral tissues 4 pair of HCC and paratumoral liver tissues are sequenced and compared
2014-08-15 | E-GEOD-55048 | biostudies-arrayexpress
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.
2011-04-09 | GSE28476 | GEO