Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA101829 | ENA |
REPOSITORIES: ENA
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Project description:This study aims on the identification of the NF-kB dependent gene regulatory network during inflammation-associated liver carcinogenesis using the well-established Mdr2 knockout mouse model. We could identify 367 differentially expressed genes comparing expression profiles of tumor samples from Mdr2-KO mice to tumor samples derived from mice with an additional hepatocyte specific expression of an IkB-superrepressor. This IkB-superrepresser is undegradable upon ubiquitinylation initialized by Ikk dependent phosphorylation and therefore impedes NFkB activity. Keywords: NFkB, IkB-superrepressor, inflammation-associated liver carcinogenesis, Mdr2-KO mouse model, hepatocellular carcinoma, gene expression, microarray
2009-05-01 | GSE13599 | GEO
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: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. The RNA samples from Mdr2-KO and control heterozygous mice aged 3 and 12M (3 males in each experimental group) were subjected to genome scale gene expression profiling with Affymetrix Mouse Array. The gene expression values were extracted with the help of MAS 5.0 software, and analyzed by cluster analysis, and by fold change filtering
2007-11-23 | E-GEOD-4612 | biostudies-arrayexpress
Project description:Adaptive mechanisms in the Mdr2-knockout mouse HCC model
| PRJNA95317 | ENA
Project description:Surgical resection is the preferred treatment for Hepatocellular carcinoma; however, it induces tumor recurrence. Our objective was to understand the molecular mechanisms linking liver regeneration under chronic-inflammation to tumorigenesis. Mdr2-knockout mice, a model of inflammation-associated cancer, underwent partial-hepatectomy which led to enhanced hepatocarcinogenesis. Yet, liver regeneration in these mice was severely attenuated. We demonstrate the activation of the DNA damage response machinery and altered genomic instability during early liver inflammatory stages resulting in hepatocyte apoptosis and cell-cycle arrest, and suggest their involvement in tumor recurrence subsequent to partial hepatectomy. We propose that under the regenerative proliferative stress induced by liver resection, the genomic unstable hepatocytes generated during chronic-inflammation, escape apoptosis and reenter the cell-cycle, triggering the enhanced tumorigenesis At present, there is a great organ shortage worldwide, thus the main treatment for Hepatocellular carcinoma (HCC) is liver resection. However, liver resection induces recurrence and mortality. In our study, we decipher, for the first time, the contribution of the DNA damage response in HCC development and recurrence, the immediate and long term effect. This is an important finding regarding the association between carcinogenesis and DNA damage response. Additionally, we demonstrate yet another link between inflammation, inducing DNA damage and genome instability, and carcinogenesis that has not been explored in the past. These results may assist in developing treatments that will reduce tumor recurrence and additionally, new prophylactic therapies during early inflammatory stages. Keywords: time course, regeneration RNA was isolated from liver samples of 9-month-old Mdr2-/- and control mice obtained on days 0 (the removed lobe), 2 and 6 following PHx. Samples of d0 were obtained from the same mice that were sacrificed on later days. As we were concerned by the variability in the KO group 6 samples were obtained for d0. All other time points and groups contained 3 samples each.
2010-01-03 | E-GEOD-14539 | biostudies-arrayexpress
Project description:Growth hormone (GH) resistance has been associated with liver cirrhosis in humans but its contribution to the disease remains controversial. In order to elucidate whether GH resistance plays a causal role in the establishment and development of liver fibrosis, or rather represents a major consequence thereof, we challenged mice lacking the Growth hormone receptor gene (Ghr-/-, a model for GH resistance) by crossing them with Mdr2 knockout mice (Mdr2-/-), a mouse model of inflammatory cholestasis and liver fibrosis. Ghr-/-;Mdr2-/- mice showed elevated serum markers associated with liver damage and cholestasis, extensive bile duct proliferation and increased collagen deposition relative to Mdr2 -/- mice, thus suggesting a more severe liver fibrosis phenotype. Additionally, Ghr-/-;Mdr2-/- mice had a pronounced down-regulation of hepato-protective genes Hnf6, Egfr and Igf-1, and significantly increased levels of ROS and apoptosis in hepatocytes, compared to control mice. Moreover, single knockout mice (Ghr-/-) fed with a diet containing 1% cholic acid displayed an increase in hepatocyte ROS production, hepatocyte apoptosis and bile infarcts compared to their wildtype littermates, indicating that loss of Ghr renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly, and despite their severe fibrotic phenotype, Ghr-/-;Mdr2-/- mice displayed a significant decrease in tumour incidence compared to Mdr2-/- mice, indicating that loss of Ghr signaling may slow the progression from fibrosis/cirrhosis to cancer in the liver.
2020-06-20 | GSE58908 | 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:We report the effect of a potent pharmacological inhibition of ASBT in mdr2 -/- mice, compared to genetic and treatment controls using RNA-sequencing. Through quantification of mRNA in liver samples, we found significant upregulation of anti-inflammatory and anti-fibrotic gene signatures in mdr2-/- mice. Additionally, we report downregulation of pro-inflammatory genes invovled in leukocyte recruitment. Mdr2 knockout mice (female, 30 day old) were fed high fat-chow diet containing a potent inhibitor of ASBT for 14 days. Genotypic and dietary controls were included. RNA-sequencing was performed on liver samples taken from the caudate lobe.
2016-02-17 | E-GEOD-66231 | biostudies-arrayexpress
Project description:Background & Aims. Resection of hepatocellular carcinoma (HCC) tumors by partial hepatectomy (PHx) is associated with promoting hepatocarcinogenesis. We have previously reported that PHx promotes hepatocarcinogenesis in the Mdr2-knockout (Mdr2-KO) mouse, a model for inflammation-mediated HCC. Now, we explored the molecular mechanisms underlying the tumor-promoting effect of PHx in these mice. Methods. Using microarrays-based techniques, we compared genomic and transcriptomic profiles of HCC tumors developing in the Mdr2-KO mice either spontaneously or following PHx. Results. PHx accelerated HCC development in these mice by four months. PHx-induced tumors had only amplifications affecting multiple chromosomes and locating mainly near the acrocentric centromeres of murine chromosomes. Four different chromosomal regions were amplified each in at least three tumors. All tumors of untreated mice had chromosomal aberrations, including both deletions and amplifications. Comparison of gene expression profiles revealed a significantly enriched expression of oncogenes, chromosomal instability markers and E2F1 targets in the post-PHx compared to spontaneous tumors. Both tumor groups shared the same frequent amplification at chromosome 18. Here, we demonstrated that one of the regulatory genes encoded by this amplified region, Crem, was over-expressed in the nuclei of murine and human HCC cells in vivo, and that it stimulated proliferation of human HCC cells in vitro. Conclusions: PHx of a chronically inflamed liver directed tumor development to a discrete pathway characterized by amplification of specific chromosomal regions and expression of specific tumor-promoting genes. Crem is a new candidate HCC oncogene frequently amplified in this model and frequently over-expressed in human HCC. To explore the mechanisms of the accelerated HCC development by PHx, we compared liver tumors and their matched non-tumor liver tissues between 9-month-old hepatectomized and 13-14-month-old untreated Mdr2-KO mice.
2015-04-01 | E-GEOD-61423 | biostudies-arrayexpress