Deletion of Pten leads to liver steatosis and tumor formation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Xiwei Wu
PROVIDER: E-GEOD-70681 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We found that deleting Pten in Albumin expressing cells results in liver steatosis as early as 1 month of age. The mice develop hyperplasia and tumor phenotypes starting at 7-8 months of age. At 12 months and beyond, all mice develope spontanous liver tumors of mixed lineage phenotypes dihydrocollidine (DDC) shows that the primary effect of AKT2 loss is attenuation of hepatic injury and not inhibition of progenitor cell proliferation in response to injury.
2015-12-31 | GSE70681 | GEO
Project description:We found that hepatic injury induced by PTEN loss establishes a selection pressure for tumorinitiating cells (TICs) to proliferate and form mixed lineage tumors. The Pten null mice demonstrate escalating levels of hepatic injury prior to proliferation of hepatic progenitors. Attenuation of hepatic injury by deleting Akt2 reduces progenitor cell proliferation and delays tumor development. Treatment of double mutant mice with 3,5-dietoxycarbonyl-1,4 dihydrocollidine (DDC) shows that the primary effect of AKT2 loss is attenuation of hepatic injury and not inhibition of progenitor cell proliferation in response to injury. Pten/Akt2 double mutant (PtenloxP/loxP; Akt2-/-; Alb-Cre+) (Dm) were generated by crossing the PtenloxP/loxP; Alb-Cre+ (Pm) with the Akt2-/- mice [19]. Control animals are PtenloxP/loxP; Albumin (Alb)-Cre-.
2016-03-31 | E-GEOD-70501 | biostudies-arrayexpress
Project description:We found that hepatic injury induced by PTEN loss establishes a selection pressure for tumorinitiating cells (TICs) to proliferate and form mixed lineage tumors. The Pten null mice demonstrate escalating levels of hepatic injury prior to proliferation of hepatic progenitors. Attenuation of hepatic injury by deleting Akt2 reduces progenitor cell proliferation and delays tumor development. Treatment of double mutant mice with 3,5-dietoxycarbonyl-1,4 dihydrocollidine (DDC) shows that the primary effect of AKT2 loss is attenuation of hepatic injury and not inhibition of progenitor cell proliferation in response to injury.
2016-03-31 | GSE70501 | GEO
Project description:Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is characterized by hepatic steatosis and hepatocellular injury and progresses to cirrhosis and hepatocellular carcinoma. Sterol regulatory element-binding proteins (SREBPs) are master regulators of lipogenesis. Liver-specific PTEN knockout (KO) mice show constitutive upregulation of SREBP through PI3K-Akt pathway activation, leading to spontaneous fatty liver and subsequent HCC development. SREBP cleavage-activating protein (SCAP) plays a critical role in SREBP activation. We sought to determine the impact of SREBP inhibition on NASH and HCC development. To this end, we additionally inhibited SREBP pathway in liver-specific PTEN mice by ablating SCAP and generated liver-specific PTEN/SCAP double KO (DKO) mice. However unexpectedly, inhibition of SCAP/SREBP pathway markedly exacerbated liver injury (5weeks), fibrosis (5months), and carcinogenesis (7 months) in PTEN KO mice. To elucidate the mechanisms of liver injury in liver-specific PTEN/SCAP DKO mice, we conducted transcriptome analyses of the livers.
2022-04-05 | GSE169104 | GEO
Project description:Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is characterized by hepatic steatosis and hepatocellular injury and progresss cirrhosis and hepatocellular carcinoma. Sterol regulatory elment-binding proteins (SREBPs) are master regulators of lipogenesis. Liver-specific PTEN knockout (KO) mice show constitutive upregulation of SREBP through PI3K-Akt pathway activation, leading to spontaneous fatty liver and subsequent HCC development. SREBP cleavage-activating protein (SCAP) plays a critical role in SREBP activation. We sought to determine the impact of SREBP inhibition on NASH and HCC development. To this end, we additionaly inhibited SREBP pathway in liver-specific PTEN mice by ablating SCAP and generated liver-specific PTEN/SCAP double KO (DKO) mice. However unexpectedly, inhibition of SCAP/SREBP pathway markedly exacerbated liver injury (5weeks), fibrosis (5months), and carcinogenesis (7 months) in PTEN KO mice. To elucidate the mechanisms of liver tumorigenesis in liver-specific PTEN/SCAP DKO mice, we conducted transcriptome analyses of the livers.
2022-04-05 | GSE174173 | GEO
Project description:1. Comparison of gene expression profiles of normal prostates and prostates isolated from 4-5 months old PSA-Cre;Pten-loxP/loxP mice<br>2.Comparison of the gene expression profile in the proximal and distal part of normal prostates
2009-08-07 | E-MEXP-2029 | biostudies-arrayexpress
Project description:Background: PTEN loss contributes to the development of many cancers and is associated with both hepatocellular carcinoma and cholangiocarcinoma. The pathogenesis of these malignancies is unclear, but they are speculated to arise from common cellular origins. We explored the influence of secondary effects, like hypoxia signaling, through co-deletion of Pten and Vhl in a murine model.Methods: We used a CreER-linked keratin 18 mouse model to conditionally delete Pten, Vhl or both, evaluating the resultant tumors by histology and gene expression microarray. A cohort of human cholangiocarcinoma samples was evaluated for relationships between HIF-1a expression and clinical outcomes.Results: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large, invasive tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl resulted in low tumor burden and reduced steatosis. Microarray analysis divided mouse tumors’ respective genotypes by gene expression. This gene expression profile grouped a human tumor cohort according to histologic type with the Pten deletion signature aligning with hepatocellular carcinoma, whereas the Pten; Vhl deletion signature associated with cholangiocarcinomas. In a human cholangiocarcinoma cohort, we observed correlation between HIF-1a expression and overall survival.Conclusions: Pten deletion leads to tumor formation and steatosis in mouse livers. Co-deletion of Vhl and Pten resulted in lower tumor burden with gene expression profiling suggesting a switch from hepatocellular expression features to an expression profile more consistent with cholangiocarinoma. A possible relation between HIF-1a expression and increased overall survival in human cholangiocarcinoma suggests that hypoxia signaling influences tumor phenotype. reference x sample
2014-10-31 | E-GEOD-55874 | biostudies-arrayexpress
Project description:PPARα act as the master of lipid metabolism in liver, however, the changes of its target genes after PHx and the effects of PPARα on regenerative genes were unknown. At 12 to 24 hours after PHx, the mice develope marked steatosis, therefore the time point of 12 hour after PHx was choosen to perform microarray analysis. We used microarray to detail the gene expression of WT (Pparafl/fl) mice and hepatocyte-specific PPARα disruption (Ppara△Hep) mice liver tissue at 12 hour after PHx or Sham operation
2018-05-10 | GSE114223 | GEO
Project description:Background and aims: Liver is a major target organ for alcohol-induced disease and the spectrum of pathological states elicited by alcohol in liver comprises steatosis, alcoholic steatohepatitis, progressive fibrosis and cirrhosis, conditions that may progress to hepatocellular carcinoma. Many experimental animal models of alcoholic steatohepatitis exist that vary in duration, mode of alcohol administration and the degree and types of liver injury produced. While most of these models, regardless whether alcohol is administered through liquid diet or intragastrically, produce steatohepatitis and mild fibrosis, it is widely acknowledged that these models fail to fully recapitulate key characteristics of severe forms of alcoholic liver disease, such as alcoholic hepatitis. Recent studies attempted to combine alcohol and fibrosis and achieved promising results in mouse models that achieve some of the key features of alcoholic liver disease accompanied by exacerbated fibrosis and acute renal injury. This study combined a chronic cholestatic liver fibrosis model induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) with a mouse model of intragastric alcohol feeding. Methods: Adult male C57BL6/J mice were treated with 3,5-diethoxycarbonyl-1,4-dihydrocolidine (DDC) containing diet (0.05% w/w) to induce chronic liver fibrosis. Following DDC-induced fibrogenesis, ethyl alcohol (EtOH) (up to 27 g/ kg/day, up to 28 days) was administered continuously to mice via a gastric feeding tube (Tsukamoto-Frenchmodel of alcoholic liver disease). Results: Exposure to DDC or EtOH alone resulted in liver fibrosis or steatosis, respectively. Combined treatment with DDC and EtOH lead to an additive effect on liver injury, as evident by the development of hepatic inflammation, steatosis, and pericellular fibrosis, and by increased serum transaminase levels, compared to mice treated with either agent alone. Liver transcriptomic changes specific to combined treatment group included pathways involved in the cell cycle and DNA damage. Analyses of feces from these mice revealed alcohol-associated changes to the bile acid profile and gut microbiome. Conclusions: Mice treated with DDC and EtOH displayed several key characteristics of human alcoholic hepatitis, including pericellular fibrosis, increased hepatic bacterial load with dysbiosis, reduced capacity of the microbiome to synthesize secondary bile acids.
2018-09-14 | GSE119953 | GEO
Project description:Background: PTEN loss contributes to the development of many cancers and is associated with both hepatocellular carcinoma and cholangiocarcinoma. The pathogenesis of these malignancies is unclear, but they are speculated to arise from common cellular origins. We explored the influence of secondary effects, like hypoxia signaling, through co-deletion of Pten and Vhl in a murine model.Methods: We used a CreER-linked keratin 18 mouse model to conditionally delete Pten, Vhl or both, evaluating the resultant tumors by histology and gene expression microarray. A cohort of human cholangiocarcinoma samples was evaluated for relationships between HIF-1a expression and clinical outcomes.Results: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large, invasive tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl resulted in low tumor burden and reduced steatosis. Microarray analysis divided mouse tumors’ respective genotypes by gene expression. This gene expression profile grouped a human tumor cohort according to histologic type with the Pten deletion signature aligning with hepatocellular carcinoma, whereas the Pten; Vhl deletion signature associated with cholangiocarcinomas. In a human cholangiocarcinoma cohort, we observed correlation between HIF-1a expression and overall survival.Conclusions: Pten deletion leads to tumor formation and steatosis in mouse livers. Co-deletion of Vhl and Pten resulted in lower tumor burden with gene expression profiling suggesting a switch from hepatocellular expression features to an expression profile more consistent with cholangiocarinoma. A possible relation between HIF-1a expression and increased overall survival in human cholangiocarcinoma suggests that hypoxia signaling influences tumor phenotype.
2014-10-31 | GSE55874 | GEO