Cholangiocarcinoma tumorigenesis in Abcb4(Mdr2)-/- and wild-type mice by transposon-based oncogenes integration
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1119438 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29264056_1.fastq.gz | Fastqsanger.gz | |||
| SRR29264056_2.fastq.gz | Fastqsanger.gz | |||
| SRR29264057_1.fastq.gz | Fastqsanger.gz | |||
| SRR29264057_2.fastq.gz | Fastqsanger.gz | |||
| SRR29264058_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 48 |
Similar Datasets
Project description:Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC), difficult to diagnose and associated with high mortality. Lack of animal models of CCA recapitulating the hepatic microenvironment of sclerosing cholangitis hinders development of novel treatments. We have developed and characterized a new mouse model of PSC-CCA through hydrodynamic tail vein injection of oncogenes pT3-EF1a-HA-myrAKT (AKT) and pT3-EF1a-YapS127A (YAP1), termed SB CCA.Mdr2-/-, which features reliable tumor induction in PSC-like background of biliary injury and fibrosis. To unravel the potential molecular profile of CCA developed in different liver context, we profiled the transcriptomes of tumor-bearing fibrotic (Mdr2-/-) (n = 6) and tumor-bearing wild-type liver tissues (n = 6) and compared to corresponding control nontumor-bearing fibrotic (Mdr2-/-) (n = 6) and healthy liver tissues (n = 6). RNA-seq analysis revealed profound transcriptional differences in CCA evolving in PSC-like context, compared to CCA in healthy liver.
2024-06-03 | GSE268905 | GEO
Project description:Chronic liver inflammation precedes the majority of hepatocellular carcinomas (HCC). Here, we explore the connection between chronic inflammation and DNA methylation in the liver at the late precancerous stages of HCC development in Mdr2/Abcb4-knockout (Mdr2-KO) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation (MeDIP) followed by hybridization with Agilent CpG Islands (CGIs) microarrays we found specific CGIs in 76 genes which were hypermethylated in the Mdr2-KO liver compared to age-matched controls. Methylation of thirty among these genes was highly specific to the studied HCC model. We revealed that in most tested cases, the observed hypermethylation resulted from an age-dependent decrease of methylation of the specific CGIs in control livers with no decrease in mutant mice. Chronic inflammation did not change global levels of DNA methylation in Mdr2-KO liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. This decrease could result from a less efficient age-dependent demethylation of specific CpG sites in the liver of Mdr2-KO mutants, as described above. Expression of some tested hypermethylated genes was increased in Mdr2-KO livers compared to controls (28%), others were either similarly expressed (44%), or not expressed in the liver (28%). Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2-KO compared to control livers affected either hepatocyte, or non-hepatocyte, or both fractions. There was only episodic correlation between changes of gene methylation and expression in cell fractions. Conclusion: Chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and non-hepatocyte liver cells. These changes may serve as markers of an increased regenerative activity and of a precancerous microenvironment in the chronically inflamed liver.
2015-03-01 | GSE64097 | GEO
Project description:Chronic liver inflammation precedes the majority of hepatocellular carcinomas (HCC). Here, we explore the connection between chronic inflammation and DNA methylation in the liver at the late precancerous stages of HCC development in Mdr2/Abcb4-knockout (Mdr2-KO) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation (MeDIP) followed by hybridization with Agilent CpG Islands (CGIs) microarrays we found specific CGIs in 76 genes which were hypermethylated in the Mdr2-KO liver compared to age-matched controls. Methylation of thirty among these genes was highly specific to the studied HCC model. We revealed that in most tested cases, the observed hypermethylation resulted from an age-dependent decrease of methylation of the specific CGIs in control livers with no decrease in mutant mice. Chronic inflammation did not change global levels of DNA methylation in Mdr2-KO liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. This decrease could result from a less efficient age-dependent demethylation of specific CpG sites in the liver of Mdr2-KO mutants, as described above. Expression of some tested hypermethylated genes was increased in Mdr2-KO livers compared to controls (28%), others were either similarly expressed (44%), or not expressed in the liver (28%). Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2-KO compared to control livers affected either hepatocyte, or non-hepatocyte, or both fractions. There was only episodic correlation between changes of gene methylation and expression in cell fractions. Conclusion: Chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and non-hepatocyte liver cells. These changes may serve as markers of an increased regenerative activity and of a precancerous microenvironment in the chronically inflamed liver. Two-condition experiment, Mdr2-KO vs Mdr2-/+ liver tissue from 12m-old male FVB strain mice. Biological replicates: 3 control replicates, 3 knockout replicates.
2015-03-01 | E-GEOD-64097 | biostudies-arrayexpress
Project description:The multidrug resistance gene 2 (Mdr2 or Abcb4) encodes a P-glycoprotein (Pgp) - a phospholipid flippase - that is the murine orthologue of the MDR3 gene in humans. The MDR2 protein is principally expressed in the bile canalicular membrane of the liver. A homozygous disruption of Abcb4 causes absence of phospholipids from bile. This phospholipid deficiency results in liver injury. The Balb-Abcb4-/- mouse strain has been generated by introgressing the Abcb4 knockout from the fibrosis-resistant FVB/NJ (FVB.129P2-Abcb4tm1Bor/J) strain into the susceptible BALB/cJ background, by backcrossing FVB- Abcb4-/- mice in to fibrosis-susceptible BALB/cJ mice for 10 generations.
2011-08-01 | GSE26699 | GEO
Project description:The multidrug resistance gene 2 (Mdr2 or Abcb4) encodes a P-glycoprotein (Pgp) - a phospholipid flippase - that is the murine orthologue of the MDR3 gene in humans. The MDR2 protein is principally expressed in the bile canalicular membrane of the liver. A homozygous disruption of Abcb4 causes absence of phospholipids from bile. This phospholipid deficiency results in liver injury. The Balb-Abcb4-/- mouse strain has been generated by introgressing the Abcb4 knockout from the fibrosis-resistant FVB/NJ (FVB.129P2-Abcb4tm1Bor/J) strain into the susceptible BALB/cJ background, by backcrossing FVB- Abcb4-/- mice in to fibrosis-susceptible BALB/cJ mice for 10 generations. cDNA expression profiling of mRNA from liver of four single male mutant mice against a pool of RNA from four wild type controls (n=8). For each mutant animal two technical replicates were performed including a dye swap experiment.
2011-07-31 | E-GEOD-26699 | biostudies-arrayexpress
Project description:We studied the molecular mechanisms of hepatocellular carcinoma (HCC) initiation and promotion using the Mdr2-knockout (Mdr2-KO) mice at pre-cancerous stages of liver disease. These mice lack the liver-specific P-glycoprotein responsible for phosphatidylcholine transport across the canalicular membrane. Portal inflammation ensues at an early age followed by the development of HCC between the ages of 12 and 15 months. Liver tissue samples of Mdr2-KO and control Mdr2-heterozygotes mice aged 3 and 12 months, were subjected to histological, biochemical and gene expression profiling analysis using Affymetrix Mouse Genome Array. Keywords: HCC, murine model, precancerous stages, chronic liver desease
2006-04-23 | GSE4612 | GEO
Project description:Mouse models of hepatocellular carcinoma (HCC) simulate specific subgroups of human HCC. We investigated hepatocarcinogenesis in Mdr2-KO mice, a model of inflammation-associated HCC, using gene expression profiling and immunohistochemical analyses. Gene expression profiling demonstrated that although Mdr2-KO mice differ from other published murine HCC models, they share several important deregulated pathways and many coordinately differentially expressed genes with human HCC datasets. Analysis of genome positions of differentially expressed genes in liver tumors revealed a prolonged region of down-regulated genes on murine chromosome 8 in three of the six analyzed tumor samples. This region is syntenic to human chromosomal regions that are frequently deleted in human HCC and harbor multiple tumor suppressor genes. Real-time RT-PCR analysis of 16 tumor samples confirmed down-regulation of several tumor suppressors in most tumors. We demonstrate that in the aged Mdr2-KO mice, cyclin D1 nuclear level is increased in dysplastic hepatocytes that do not form nodules; however, it is decreased in dysplastic nodules and in liver tumors. We found that this decrease is mostly at the protein, rather than the mRNA level. These findings raise the question on the role of cyclin D1 at early stages of hepatocarcinogenesis in the Mdr2-KO HCC model. Furthermore, we show that most liver tumors in Mdr2-KO mice were characterized by the absence of b-catenin activation. In conclusion, the Mdr2-KO mouse may serve as a model for b-catenin-negative subgroup of human HCCs characterized by low nuclear cyclin D1 levels in tumor cells and by down-regulation of multiple tumor suppressor genes. Keywords: Hepatocellular carcinoma, Mouse model, Mdr2-knockout.
2007-10-10 | GSE8642 | GEO
Project description:Whole Genome sequencing of Mdr2-knockout
| PRJNA243010 | ENA
Project description:Chronic inflammation is a common underlying condition associated with tumor development, accounting for approximately 20% of human cancers. This association is especially apparent in Hepatocellular carcinoma (HCC), which often develops on the background of chronic hepatitis and hepatic fibrosis, slowly unfolding on a background of chronic inflammation. HCC is one of the most common tumors worldwide, exhibiting a very poor prognosis and high mortality rate with limited available therapeutic tools. The etiology of liver cancer is well known, however there is still a lack of precise knowledge about pathogenesis of HCC. IL-6 have been shown to be of importance for liver protection and prevention of liver injury in animal models of acute sclerosing cholangitis and correlate with increased HCC in human patients. Using a murine model of chronic cholangitis based on the ablation of the Mdr2 gene, this study has examined the role of IL-6 signaling in chronic hepatitis and in the subsequent development of liver cancer. The main observations of this study are that IL-6 signaling in male Mdr2-KO mice protects from the development of liver injury and fibrosis, but simultaneously promotes tumor initiation. Thus, IL-6 deficiency in male Mdr2-KO mice dissociates the tight correlation between liver fibrosis and the development of inflammation-associated HCC. To reveal the affected molecular pathways that lead to increased cholestasis and bile acid–induced liver injury, but reduced tumorigenesis in the male IL-6 deficient Mdr2-KO/IL6-KO mice, we performed gene array analysis and identified distinct classes of differentially-expressed genes in these mice. We performed genome-scale gene expression profiling by Affymetrix analysis on tumor-free livers samples from Mdr2-KO, Mdr2-KO/IL6-KO, and wild type C57BL/6 mice at the age of 14 months.
2015-05-01 | E-GEOD-37468 | biostudies-arrayexpress