Mus musculus
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-46821
PROVIDER: PRJNA202403 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Prdm5 suppresses ApcMin-driven intestinal adenomas and regulates monoacylglycerol lipase expression
2015-07-13 | E-GEOD-46821 | ExpressionAtlas
Project description:PRDM proteins are tissue specific transcription factors often deregulated in diseases, particularly in cancer where different members have been found to act as oncogenes or tumor suppressors. PRDM5 is a poorly characterized member of the PRDM family for which several studies have reported a high frequency of promoter hypermethylation in cancers of gastrointestinal origin. We report here the characterization of Prdm5 knockout mice in the context of intestinal carcinogenesis. We demonstrate that loss of Prdm5 increases the number of adenomas throughout the murine small intestine on an ApcMin background. By genome-wide ChIP-seq and transcriptome analyses we identify loci encoding proteins involved in metabolic processes as prominent PRDM5 targets and characterize monoacylglycerol lipase (Mgll) as a direct PRDM5 target in human colon cancer cells and in Prdm5 mutant mouse intestines. Moreover, we report the downregulation of PRDM5 protein expression in human colon neoplastic lesions. In summary, our data provide the first causal link between Prdm5 loss and intestinal carcinogenesis and uncover an extensive and novel PRDM5 target repertoire likely facilitating the tumor suppressive functions of PRDM5. Two experimental conditions: wt and ko mice for PRDM5. Each experimental condition was replicated three times. This submission represents transcriptome component of study.
2013-05-11 | E-GEOD-46821 | biostudies-arrayexpress
Project description:PRDM proteins are tissue specific transcription factors often deregulated in diseases, particularly in cancer where different members have been found to act as oncogenes or tumor suppressors. PRDM5 is a poorly characterized member of the PRDM family for which several studies have reported a high frequency of promoter hypermethylation in cancers of gastrointestinal origin. We report here the characterization of Prdm5 knockout mice in the context of intestinal carcinogenesis. We demonstrate that loss of Prdm5 increases the number of adenomas throughout the murine small intestine on an ApcMin background. By genome-wide ChIP-seq and transcriptome analyses we identify loci encoding proteins involved in metabolic processes as prominent PRDM5 targets and characterize monoacylglycerol lipase (Mgll) as a direct PRDM5 target in human colon cancer cells and in Prdm5 mutant mouse intestines. Moreover, we report the downregulation of PRDM5 protein expression in human colon neoplastic lesions. In summary, our data provide the first causal link between Prdm5 loss and intestinal carcinogenesis and uncover an extensive and novel PRDM5 target repertoire likely facilitating the tumor suppressive functions of PRDM5.
2013-05-11 | GSE46821 | GEO
Project description:The Notch signaling pathway regulates fate decision, proliferation and differentiation of intestinal epithelial cells. However, the role of Notch signaling in colorectal cancer progression is largely unknown. Here we show that Notch signaling suppresses the progression of colorectal tumorigenesis, even though it augments tumor initiation. In contrast to adenomas of Apcmin mice, Notch-inactivated Apcmin adenomas showed more malignant characteristics, such as submucosal invasion and loss of glandular pattern. Conversely, Notch-activated Apcmin adenomas showed a reversion from high-grade to low-grade features, such as the restoration of adherent junctions. Expression profiling revealed that Notch signaling promotes the differentiation of tumor cells with down regulation of Wnt/beta-catenin target genes and inhibition of epithelial-mesenchymal transition. Comparison of mouse and human expression profiles also suggests the common role of Notch in inhibition of tumor progression. Interestingly, Notch signaling suppressed the expression of beta-catenin responsive genes through chromatin modification of Tcf4/beta-catenin binding sides. Our results suggest that Notch signaling has dual roles in colorectal tumorigenesis: promoting adenoma initiation, while inhibiting tumor progression to colorectal cancer. mRNAs from normal (WT, Notch-activated and Notch-inactivated) and tumor (WT, Notch-activated and Notch-inactivated) tissues were profiled.
2011-04-19 | E-GEOD-21392 | biostudies-arrayexpress
Project description:The Notch signaling pathway regulates fate decision, proliferation and differentiation of intestinal epithelial cells. However, the role of Notch signaling in colorectal cancer progression is largely unknown. Here we show that Notch signaling suppresses the progression of colorectal tumorigenesis, even though it augments tumor initiation. In contrast to adenomas of Apcmin mice, Notch-inactivated Apcmin adenomas showed more malignant characteristics, such as submucosal invasion and loss of glandular pattern. Conversely, Notch-activated Apcmin adenomas showed a reversion from high-grade to low-grade features, such as the restoration of adherent junctions. Expression profiling revealed that Notch signaling promotes the differentiation of tumor cells with down regulation of Wnt/beta-catenin target genes and inhibition of epithelial-mesenchymal transition. Comparison of mouse and human expression profiles also suggests the common role of Notch in inhibition of tumor progression. Interestingly, Notch signaling suppressed the expression of beta-catenin responsive genes through chromatin modification of Tcf4/beta-catenin binding sides. Our results suggest that Notch signaling has dual roles in colorectal tumorigenesis: promoting adenoma initiation, while inhibiting tumor progression to colorectal cancer.
2011-04-19 | GSE21392 | GEO
Project description:Aberrant DNA methylation is frequent in colorectal cancer (CRC), but the underlying mechanisms and pathological consequences are poorly understood. Ten-Eleven Translocation (TET) dioxygenases and Thymine DNA Glycosylase (TDG) mediate active DNA demethylation by generating and removing oxidized cytosine species. TET1 and TDG mutations, and altered levels of oxidized cytosines have been identified in human CRC. To investigate the TET-TDG demethylation axis in intestinal tumorigenesis, we generated ApcMin mice that are devoid of Tet1 and/or Tdg, and characterized the methylome and transcriptome of intestinal adenomas. There were increased numbers (>30) of adenomas in ApcMin mice expressing the dominant-negative TdgN151A allele, whereas Tet1-deficient and Tet1/Tdg-double heterozygous ApcMin adenomas were larger and displayed features of erosion and invasion. Methylome analysis revealed reduction in global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-mutant ApcMin mice, and hypermethylation of CpG islands in Tet1-mutant ApcMin mice. In addition, RNA sequencing showed upregulation of inflammatory, immune and interferon response genes in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. The corresponding 127-gene inflammatory signature separated human colonic adenocarcinomas in four groups, closely aligned with their microsatellite or chromosomal instability, and characterized by different levels of DNA methylation and DNMT1 expression that anti-correlated with TET1 expression. These findings demonstrate a novel mechanism of epigenetic regulation during intestinal tumorigenesis by which TET1-TDG-mediated DNA demethylation may decrease methylation levels and inflammatory/interferon/immune responses, and is linked to the type of genomic instability.
2024-07-01 | GSE179313 | GEO
Project description:We constructed AAV-vectors for systemic expression of a soluble RSPO1 protein in ApcMin/+ mice. We found that the RSPO1-Fc fusion protein suppresses the Wnt/ß-catenin signaling activity in intestinal adenomas and in adenoma-derived intestinal organoids ex vivo, but not in normal intestinal epithelial cells. In the Apc mutant cells, the RSPO1-Fc fusion protein activated the TGFß/SMAD signaling pathway to suppress several Wnt target genes and adenoma growth, which effect was rescued suppressed by the TGFß receptor kinase inhibitor SB-431542. Simultaneously, RSPO1-Fc induced proliferation of the normal intestinal stem cells, giving them a growth advantage over the mutant cells, which enabled the intestinal epithelium to eventually outgrow the adenoma cells. Prolonged systemic expression of AAV-RSPO1-Fc decreased significantly the number of the intestinal adenomas and improved the overall survival of ApcMin/+ mice. Thus RSPO1-Fc provides the normal intestinal epithelial cells a growth advantage when compared to the adenoma cells, which eventually leads to the extrusion of the adenomatous tissue. An attractive idea now is to exploit such differential response of normal vs. cancer cells in cancer therapy.
2020-02-29 | GSE146099 | GEO
Project description:We constructed AAV-vectors for systemic expression of a soluble RSPO1 protein in ApcMin/+ mice. We found that the RSPO1-Fc fusion protein suppresses the Wnt/ß-catenin signaling activity in intestinal adenomas and in adenoma-derived intestinal organoids ex vivo, but not in normal intestinal epithelial cells. In the Apc mutant cells, the RSPO1-Fc fusion protein activated the TGFß/SMAD signaling pathway to suppress several Wnt target genes and adenoma growth, which effect was rescued suppressed by the TGFß receptor kinase inhibitor SB-431542. Simultaneously, RSPO1-Fc induced proliferation of the normal intestinal stem cells, giving them a growth advantage over the mutant cells, which enabled the intestinal epithelium to eventually outgrow the adenoma cells. Prolonged systemic expression of AAV-RSPO1-Fc decreased significantly the number of the intestinal adenomas and improved the overall survival of ApcMin/+ mice. Thus RSPO1-Fc provides the normal intestinal epithelial cells a growth advantage when compared to the adenoma cells, which eventually leads to the extrusion of the adenomatous tissue. An attractive idea now is to exploit such differential response of normal vs. cancer cells in cancer therapy.
2020-03-01 | GSE146138 | GEO
Project description:Background and aims: The transcription factor Stat3 has been considered to promote progression and metastasis of intestinal cancers. Methods: We investigated the role of Stat3 in intestinal tumors using mice with conditional ablation of Stat3 in intestinal epithelial cells (Stat3deltaIEC). Results: In the APCmin mouse model of intestinal cancer, genetic ablation of Stat3 reduced the multiplicity of early adenomas. However, loss of Stat3 promoted tumor progression at later stages leading to formation of invasive carcinomas which significantly shortened the lifespan of Stat3deltaIEC APCmin/+ mice. Interestingly, loss of Stat3 in tumors of APCmin/+ mice had no significant impact on cell survival and angiogenesis but promoted cell proliferation. A genome-wide expression analysis of Stat3-deficient tumors suggested that Stat3 negatively regulates intestinal cancer progression via the cell adhesion molecule Ceacam1. Conclusions: Our data suggest that Stat3 impairs progression of intestinal tumors. Therefore, detrimental effects on tumor progression have to be considered upon therapeutic targeting of the Stat3 signaling pathway in intestinal cancer.
2009-12-01 | GSE17841 | GEO
Project description:The interferon-inducible transcription factor STAT1 is a tumor suppressor in various malignancies. We investigated STAT1 functions in intestinal tumorigenesis of ApcMin mice. Surprisingly, loss of STAT1 in intestinal epithelial cells (STAT1ΔIEC) interfered with ApcMin induced intestinal tumor formation and tumor progression. RNASeq data demonstrated reduced expression of Indoleamine-2,3-dioxygenase-1 (IDO1) in STAT1ΔIEC ApcMin tumors. IDO1 is implicated in synthesis of kynurenine, a metabolite that induces ß-Catenin nuclear localisation and suppresses anti-tumor immune responses.
2020-04-05 | E-MTAB-5083 | biostudies-arrayexpress