AP4 regulates stem and Paneth cell homeostasis and promotes adenoma initiation in the intestine (adenoma)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE99437 | GEO | 2018/12/25
REPOSITORIES: GEO
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Project description:AP4 is frequently expressed in primary CRCs. However, the in vivo relevance of AP4 for development of intestinal tumor formation has not been analyzed by genetic approaches. ApcMin/+ mice with deletion of AP4 were generated and analyzed. The mRNA expression profiles of intestinal adenomas with and without functional AP4 were compared.
2018-12-25 | GSE99434 | GEO
Project description:miR-34a and miR-34b/c genes are frequently epigenetically silenced in primary CRCs. However, the in vivo relevance of miR-34a/b/c for suppression of intestinal tumor formation has not been analyzed by genetic approaches. ApcMin/+ mice with deletion of the miR-34a and miR-34b/c genes were generated and analyzed. The mRNA expression profiles of intestinal adenomas with and without functional miR-34a/b/c genes were compared.
2017-05-28 | GSE84138 | GEO
Project description:To address the in vivo relevance of CSF1R regulation by miR-34a during intestinal tumor formation, we generated ApcMin/+ mice with intestinal-epithelial cell (IEC)-specific deletions of the Mir34a and/or Csf1r genes. The mRNA expression profiles of intestinal adenomas with and without functional miR-34a and/or Csf1r were compared.
2022-10-04 | GSE167448 | 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:We report that colon adenomas from ApcMin/+ mice not only exhibit similarities in gene expression profile to colon adenomas from azoxymethane / dextran sulfate sodium-treated mice (with activating Ctnnb1 mutations) due to the activation of canonical WNT signaling, but also unique transcriptional changes in the pathways regulating cell cycle progression / proliferation, chromosome segregation / cytoskeletal organization and apoptosis. Subsequent experiments characterized changes in gene expression unique to colon adenomas from ApcMin/+ mice including increases in the H2afv, Map6 and Nsmf transcripts.
2017-12-13 | GSE98496 | GEO
Project description:The transcription factor Zinc finger protein 148 (Zfp148) interacts physically with the tumor suppressor p53, but the siginficance of this interaction is not known. We recently showed that knockout of Zfp148 in mice leads to ectopic activation of p53 in tissues and cultured fibroblasts, suggesting that Zfp148 represses p53 activity. Here we hypothesized that targeting Zfp148 would unleash p53 activity and protect against cancer development, and test this idea in the APCMin/+ mouse model of intestinal adenomas. Crypt-enriched tissues were isolated by laser microdissection (PALM) from the small intestines (proximal) of Zfp148gt/+APCMin/+ and Zfp148+/+APCMin/+ mice for RNA extraction and hybridization to Affymetrix microarrays.
2016-02-10 | E-GEOD-77773 | biostudies-arrayexpress
Project description:Fecal immunochemical tests (FIT) detecting hemoglobin in stool are widely used for non-invasive colorectal cancer (CRC) screening, but their sensitivity leaves room for improvement. Our aim is to identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRCs and advanced adenomas (AAs). Stool samples (one series of 12 CRCs and 10 controls, and a second series of 81 CRCs, 40 AAs, 43 non-advanced adenomas and 129 controls) were analyzed by mass-spectrometry and searched for human proteins. Classification and regression tree and logistic regression analyses were performed to identify protein combinations that differentiated CRCs and/or AAs from controls. Antibody-based assays for four selected proteins were performed on an independent series of FIT samples (14 CRCs, 16 AAs, 18 non-advanced adenomas and 24 controls) Results: In total, 834 human proteins were identified, of which 29 were significantly enriched in CRCs versus controls in both stool sample series. Combinations of four proteins reached sensitivities of 80% and 45% for detecting CRCs and AAs, at 95% specificity, which was higher than hemoglobin alone.
2020-05-26 | PXD007767 | Pride
Project description:The transcription factor Zinc finger protein 148 (Zfp148) interacts physically with the tumor suppressor p53, but the siginficance of this interaction is not known. We recently showed that knockout of Zfp148 in mice leads to ectopic activation of p53 in tissues and cultured fibroblasts, suggesting that Zfp148 represses p53 activity. Here we hypothesized that targeting Zfp148 would unleash p53 activity and protect against cancer development, and test this idea in the APCMin/+ mouse model of intestinal adenomas.
2016-02-10 | GSE77773 | GEO
Project description:Aberrant DNA methylation is frequently observed in colorectal cancer (CRC), but the underlying mechanisms and pathological consequences are poorly understood. Ten-Eleven Translocation (TET) dioxygenases and Thymine DNA Glycosylase (TDG) are involved in active DNA demethylation by generating and removing novel oxidized cytosine species. TET1 and TDG mutations, and alterations of the levels of oxidized cytosines have been identified in human CRC. To clarify the biological significance of 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 by DREAM and RNA sequencing, respectively. Tet1-deficient and Tet1/Tdg-double heterozygous ApcMin adenomas manifested increased adenoma size and features of erosion or invasion, whereas an increased number (>30) of adenomas was found in Tdg-mutant ApcMin mice. Methylome analysis revealed progressive loss of global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-deficient ApcMin mice, and hypermethylation of CpG islands in Tet1-deficient ApcMin mice. In addition, RNA sequencing showed upregulation of genes in inflammatory, immune and interferon response in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. The corresponding 135-gene inflammatory signature separated human colonic adenocarcinomas into four groups, closely aligned with their microsatellite or chromosomal instability profile, and characterized by different levels of DNA methylation and DNMT1 expression levels that anti-correlated with TET1 expression levels. These findings demonstrate a novel mechanism of epigenetic regulation during intestinal tumorigenesis by which TET1-TDG-mediated active DNA demethylation decreases not only methylation levels, but also inflammatory/interferon/immune response, which impinges on the intrinsic features of genomic instability of the tumors. This study establishes a novel link, via inflammatory response, between epigenomic and genomic instability.
2023-10-01 | GSE179526 | GEO