Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA110215 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: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: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. Experiment Overall Design: The liver RNA samples from six Mdr2-KO tumors, six non-tumorous liver tissues (four matched and two unmatched), as well as from three control heterozygous mice at 16 months of age were subjected to gene expression profiling using the genome scale Affymetrix Mouse Genome 430 2.0 Array.
2008-06-16 | E-GEOD-8642 | 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. 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: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: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
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 female Mdr2-KO mice protects from the development of liver injury and fibrosis, but simultaneously reduced tumor initiation. To reveal the affected molecular pathways that lead to increased cholestasis and bile acid ?induced liver injury, and increased tumorigenesis in the female 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-37559 | 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
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