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Series GSE9549 Query DataSets for GSE9549
Status Public on Dec 12, 2007
Title Regulation of Liver Regeneration and Hepatocarcinogenesis by Suppressor of Cytokine Signaling 3
Organism Mus musculus
Experiment type Expression profiling by array
Summary 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.
Keywords: SOCS3, liver regeneration
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.
Contributor(s) Beyer RP
Citation(s) 18158318
Submission date Nov 08, 2007
Last update date Feb 11, 2019
Contact name James William MacDonald
Organization name University of Washington
Department Environmental and Occupational Health Sciences
Street address 4225 Roosevelt Way NE
City Seattle
State/province WA
ZIP/Postal code 98105-6099
Country USA
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (6)
GSM241738 SOCS3 Cre minus A
GSM241739 SOCS3 Cre plus A
GSM241740 SOCS3 Cre minus B
BioProject PRJNA103365

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Supplementary file Size Download File type/resource
GSE9549_RAW.tar 36.4 Mb (http)(custom) TAR (of CEL)
Raw data provided as supplementary file
Processed data included within Sample table

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