Expression data from GNMT and MAT1A knockout models that develop all the stages of non-alcoholic fatty liver disease including hepatocellular carcinoma [GNMT_MAT1A_3&8_months]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE63027 | GEO | 2014/11/07
SECONDARY ACCESSION(S): PRJNA266542
REPOSITORIES: GEO
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Project description:Liver global gene expression patterns of 15-month-old MAT1A knockout mice histopathologically determined to have hepatocellular carcinoma (HCC). 5 samples are of tumoral tissue and 5 samples are of peritumoral tissue. All these have their respective wild type patterns. These were analyzed to define signatures to study the pathogenesis of NAFLD-derived HCC, explore which subtypes of cancers can be investigated using mouse models and define a signature of HCC differential survival that can be used to characterize HCC subtypes of different survival derived from mixed etiologies.
2014-11-07 | GSE63062 | GEO
Project description:We report that 7 of 7 female Gnmt-/- mice developed hepatocellular carcinoma (HCC), the most common form of liver cancer, at the mean age of 16.1 months. In contrast, only one-third (2/6) of male Gnmt-/- mice had HCC, the remaining had either premature death or liver necrosis. Microarray analysis showed that genes involved in the following pathways were deregulated in different stages of tumorigenesis: S-adenosylmethionine (SAM)-dependent methyltransferases, metabolism, signal transduction, cell proliferation, cell adhesion and immune responses. This study reveals that GNMT plays an important role in the prevention of hapatotumorigenesis through regulating DNA methylaiton and oxidative stress signaling pathways. We postulate that GNMT is a stress-responsive protein and its expression may account for the gender difference of the susceptibility to liver cancer. Keywords: Gnmt knockout
2008-12-01 | GSE9809 | GEO
Project description:Hepatocellular carcinoma (HCC) is the first cause of death in cirrhotic patients. Liver cirrhosis at a high risk of HCC has abnormal S-Adenosylmethionine (SAMe) levels. Catabolism of SAMe is mainly mediated by Glycine N-methyltransferase (GNMT), Lack in GNMT expression leads to epigenetic regulation of critical carcinogenesis pathways and mounting evidence assigns an essential role of GNMT in HCC. Methods: Here we have studied the role of LKB1-AMPK and RAS in the proliferation and transformation of GNMT-deficient HCC. Results. GNMT-deficient HCC was characterized by LKB1-AMPK misconnection, leading to resistance of apoptosis response mediated by a positive regulation of cAMP-PKA-CaMKKβ cascade. Additionally, Ras-mediated hyperactivation of LKB1 contributes to the proliferation of GNMT-deficient HCC in an ERK/p90RSK-dependent manner. The observed LKB1-induced Ras activation, was due to the regulation of RASGRP3 expression. Notably, the human HCC tumors with poorer prognosis showed the lowest levels of GNMT, p-AMPKα(Thr172) and the highest activation of Ras/LKB1/RASGRP3 axis. The present data suggest a correlation between LKB1 and RAS activity in a context of HCC with low GNMT expression, indicating that activation of the RAS/LKB1/RASGRP3 cascade might possess an important prognostic role in human liver cancer. Furthermore, these findings open the possibility to design new therapeutic strategies for the treatment of liver cancer.
2012-07-01 | GSE34838 | GEO
Project description:We report that 7 of 7 female Gnmt-/- mice developed hepatocellular carcinoma (HCC), the most common form of liver cancer, at the mean age of 16.1 months. In contrast, only one-third (2/6) of male Gnmt-/- mice had HCC, the remaining had either premature death or liver necrosis. Microarray analysis showed that genes involved in the following pathways were deregulated in different stages of tumorigenesis: S-adenosylmethionine (SAM)-dependent methyltransferases, metabolism, signal transduction, cell proliferation, cell adhesion and immune responses. This study reveals that GNMT plays an important role in the prevention of hapatotumorigenesis through regulating DNA methylaiton and oxidative stress signaling pathways. We postulate that GNMT is a stress-responsive protein and its expression may account for the gender difference of the susceptibility to liver cancer. Keywords: Gnmt knockout Liver tissues from wild-type or Gnmt knockout mice at young ages, devoloping dysplasia nodules or HCC were used for RNA extraction and hybridization on Affymetrix microarrays. For 11 weeks old mice, total RNA were mixed in equal proportion from 3 mice.
2008-12-01 | E-GEOD-9809 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) is the first cause of death in cirrhotic patients. Liver cirrhosis at a high risk of HCC has abnormal S-Adenosylmethionine (SAMe) levels. Catabolism of SAMe is mainly mediated by Glycine N-methyltransferase (GNMT), Lack in GNMT expression leads to epigenetic regulation of critical carcinogenesis pathways and mounting evidence assigns an essential role of GNMT in HCC. Methods: Here we have studied the role of LKB1-AMPK and RAS in the proliferation and transformation of GNMT-deficient HCC. Results. GNMT-deficient HCC was characterized by LKB1-AMPK misconnection, leading to resistance of apoptosis response mediated by a positive regulation of cAMP-PKA-CaMKKM-NM-2 cascade. Additionally, Ras-mediated hyperactivation of LKB1 contributes to the proliferation of GNMT-deficient HCC in an ERK/p90RSK-dependent manner. The observed LKB1-induced Ras activation, was due to the regulation of RASGRP3 expression. Notably, the human HCC tumors with poorer prognosis showed the lowest levels of GNMT, p-AMPKM-NM-1(Thr172) and the highest activation of Ras/LKB1/RASGRP3 axis. The present data suggest a correlation between LKB1 and RAS activity in a context of HCC with low GNMT expression, indicating that activation of the RAS/LKB1/RASGRP3 cascade might possess an important prognostic role in human liver cancer. Furthermore, these findings open the possibility to design new therapeutic strategies for the treatment of liver cancer. HCC induced wild-type or Gnmt knockout mice at 3 weeks old were used for RNA extraction and hybridization on Illumina microarrays. The study comprises three groups of samples: OKER cell line(n=3), GNMT-KO mouse hepatocytes (n=3) ,GNMT-WT mouse hepatocytes(n=3)
2012-06-30 | E-GEOD-34838 | biostudies-arrayexpress
Project description:We report that liver nodules from 5/8 (62.5%) male and 4/5 (80%) female Gnmt-/- mice were diagnosed as having HCC. Microarray analysis showed that genes involved in the following pathways were deregulated in different stages of tumorigenesis: Methylation, metabolism, signal transduction, cell proliferation, and cell adhesion. This study reveals that GNMT plays an important role in the prevention of hepatotumorigenesis through regulating detoxification pathways. We postulate that GNMT is a stress-responsive protein and its expression may account for the gender difference of the susceptibility to liver cancer.
2009-10-02 | GSE18218 | GEO
Project description:Methionine adenosyltransferase (MAT) enzymes generate SAMe (S-adenosylmethionine), the main biological methyl donor. There are two MAT encoding genes in mammals (Mat1a and Mat2a), which show different activities and cellular distribution. Mat1a encodes the enzyme mainly expressed in normal liver. Mat1a ablation in mice results in the spontaneous development of non-alcoholic steatohepatitis (NASH). We observed that SAMe depletion in Mat1a KO mice had three main effects on hepatic lipid metabolism: 1) impaired TG (triglyceride) export via VLDL; 2) impaired mitochondrial FA (fatty acid) oxidation (as evidenced by membrane depolarization, downregulation of Phb1 (prohibitin 1, a mitochondrial chaperone protein) and Mcj/Dnajc15 (endogenous mitochondrial repressor of respiratory chain), and accumulation of long-chain acylcarnitines); and 3) increased FA uptake. The convergence of these three factors induced TG accumulation in LD (lipid droplets). LD expansion confronts hepatocytes with a high demand of PC (phosphatidylcholine) molecules to cover the LD surface since other phospholipids, such as PE (phosphatidylethanolamine), cannot stabilize LD and prevent coalescence. In Mat1a KO this situation is aggravated, since SAMe-dependent PC synthesis via PE methylation is decreased, the PC/PE ratio reduced and mitochondrial FA oxidation impaired. To put a brake to this drain of PC molecules to LD, FA are rerouted in Mat1a KO mice liver to other catabolic (endoplasmic reticulum and peroxisome oxidation) and biosynthetic (ceramides synthesis) pathways, causing oxidative stress, inflammation and fibrosis. SAMe treatment for two months in 8-9 month old Mat1a KO mice ameliorated mitochondrial dysfunction (reduces membrane depolarization, improves Phb1 and Mcj expression, and increases SAMe transport to mitochondria) improving FA oxidation efficiency (FA and acylcarnitine levels decrease), which results in a drastic reduction in TG accumulation. SAMe treatment in Mat1a KO mice resulted in more PC available for proper membrane function, improving liver lipid homeostasis, histology (H&E, Sudan red, Sirius red) and liver injury (ALT, AST).
2017-02-02 | GSE77082 | GEO
Project description:Methionine adenosyltransferase (MAT) enzymes generate SAMe (S-adenosylmethionine), the main biological methyl donor. There are two MAT encoding genes in mammals (Mat1a and Mat2a), which show different activities and cellular distribution. Mat1a encodes the enzyme mainly expressed in normal liver. Mat1a ablation in mice results in the spontaneous development of non-alcoholic steatohepatitis (NASH). We observed that SAMe depletion in Mat1a KO mice had three main effects on hepatic lipid metabolism: 1) impaired TG (triglyceride) export via VLDL; 2) impaired mitochondrial FA (fatty acid) oxidation (as evidenced by membrane depolarization, downregulation of Phb1 (prohibitin 1, a mitochondrial chaperone protein) and Mcj/Dnajc15 (endogenous mitochondrial repressor of respiratory chain), and accumulation of long-chain acylcarnitines); and 3) increased FA uptake. The convergence of these three factors induced TG accumulation in LD (lipid droplets). LD expansion confronts hepatocytes with a high demand of PC (phosphatidylcholine) molecules to cover the LD surface since other phospholipids, such as PE (phosphatidylethanolamine), cannot stabilize LD and prevent coalescence. In Mat1a KO this situation is aggravated, since SAMe-dependent PC synthesis via PE methylation is decreased, the PC/PE ratio reduced and mitochondrial FA oxidation impaired. To put a brake to this drain of PC molecules to LD, FA are rerouted in Mat1a KO mice liver to other catabolic (endoplasmic reticulum and peroxisome oxidation) and biosynthetic (ceramides synthesis) pathways, causing oxidative stress, inflammation and fibrosis. SAMe treatment for two months in 8-9 month old Mat1a KO mice ameliorated mitochondrial dysfunction (reduces membrane depolarization, improves Phb1 and Mcj expression, and increases SAMe transport to mitochondria) improving FA oxidation efficiency (FA and acylcarnitine levels decrease), which results in a drastic reduction in TG accumulation. SAMe treatment in Mat1a KO mice resulted in more PC available for proper membrane function, improving liver lipid homeostasis, histology (H&E, Sudan red, Sirius red) and liver injury (ALT, AST).
2017-02-02 | GSE77079 | GEO
Project description:We report that liver nodules from 5/8 (62.5%) male and 4/5 (80%) female Gnmt-/- mice were diagnosed as having HCC. Microarray analysis showed that genes involved in the following pathways were deregulated in different stages of tumorigenesis: Methylation, metabolism, signal transduction, cell proliferation, and cell adhesion. This study reveals that GNMT plays an important role in the prevention of hepatotumorigenesis through regulating detoxification pathways. We postulate that GNMT is a stress-responsive protein and its expression may account for the gender difference of the susceptibility to liver cancer. Liver tissues from aflatoxin B1 (AFB1)-treated wild-type or Gnmt knockout mice at 11weeks old were used for RNA extraction and hybridization on Affymetrix microarrays. Total RNA were mixed in equal proportion from 3 mice.
2009-10-02 | E-GEOD-18218 | biostudies-arrayexpress
Project description:We report that Gnmt-/- mice have abnormal behavior including spontaneous locomotion activity, PPI, TST and FST. Microarray analysis showed that genes expression profiles in male Gnmt -/- mice Keywords: Gnmt knockout
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