Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Cyld CGH

ABSTRACT: In order to identify the function of the tumor suppressor CYLD in liver, we generate a liver specific disruption of this gene in mouse (liver specific CYLD KO mice). In our analysis it was revealed that these mice initially develop fibrosis and finally they develop spontaneous liver cancer after 1 year of age. We performed CGH analysis in 8 different tumor foci from the tumor livers of 4 different CYLD liver specific KO animals, in comparison to wild type reference liver DNA. From every tumor liver, two cancer foci was microdissected. Cancer foci samples with IDs: DS-071_01 and DS-071_02 are from liver specific CYLD KO animal #1, DS-071_03 and DS-071_04 are from liver specific CYLD KO animal #2, DS-071_05 and DS-071_06 are from liver specific CYLD KO animal #3, DS-071_07 and DS-071_08 are from liver specific CYLD KO animal #4. Liver genomic DNA from cancer samples and from a reference wild type liver was extracted (Qiagen) and CGH analysis was performed to determine DNA copy number changes (IMGM Laboratories, Germany). This analysis revealed a large number of amplifications and deletions ranging from 0,62Mb to 14,8Mb in all chromosomes.

ORGANISM(S): mus_musculus

SUBMITTER: Kostas Nikolaou

PROVIDER: E-MTAB-905 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Suppressor of cytokine signaling 3 (SOCS3) down-regulates several signaling pathways in multiple cell types, and previous data suggest that SOCS3 may shut off cytokine activation at the early stages of liver regeneration. We developed hepatocyte-specific Socs3 knockout (Socs3 h-KO) mice to directly study the role of SOCS3 during liver regeneration after 2/3 partial hepatectomy (PH). Socs3 h-KO mice demonstrate marked enhancement of DNA replication and liver weight restoration after 2/3 PH in comparison with littermate controls. Without SOCS3, signal transducer and activator of transcription 3 (STAT3) phosphorylation is prolonged, and activation of the mitogenic kinases extracellular signal-regulated kinase 1/2 (ERK1/2) is enhanced after PH. In vitro, we show that SOCS3 deficiency enhances hepatocyte proliferation in association with enhanced STAT3 and ERK activation after epidermal growth factor (EGF) or interleukin 6 (IL-6) stimulation. Microarray analyses show that SOCS3 modulates a distinct set of genes after PH, which fall into diverse physiologic categories. Using a model of chemical-induced carcinogenesis, we found that Socs3 h-KO mice develop hepatocellular carcinoma (HCC) at an accelerated rate. By acting on cytokines and multiple proliferative pathways, SOCS3 modulates both physiologic and neoplastic proliferative processes in the liver, and may act as a tumor suppressor. Experiment Overall Design: Hepatocyte-specific excision of the Socs3 gene was achieved by breeding Socs3 fl/fl mice with mice expressing the Cre recombinase transgene under control of the albumin promoter (Alb-Cre+), yielding Socs3 h-KO mice. Socs3 fl/fl, Alb-Cre- littermates were used as controls for all experiments, and are henceforth referred to as littermates. All mice (C57BL/6) were free of Helicobacter species, housed in a specific pathogen free facility with 12-h light/dark cycles with free access to standard food and water. 2/3 PH and sham operations were performed as previously described (15, 50) (n=3-6 mice per genotype per time point). Liver remnants were weighed after removal of necrotic stumps and sutures, and compared to post-operative body weight. For HCC experiments, a single i.p. injection of DEN (5mg/kg, Sigma) was performed 12-14 d after birth. For short time points, a single injection of DEN (100mg/kg) (31) was given to 4 wk old mice. At indicated time points, mice were sacrificed by CO2 inhalation. All animal studies were carried out under approved IACUC protocols at the University of Washington.

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Cyld CGH

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