Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methionine adenosyltransferase (MAT) catalyzes the formation of S-adenosylmethionine (SAM), the principal methyl donor, and is essential to normal cell function. The two forms of MAT, liver specific and non-liver specific, are products of two genes, MAT1A and MAT2A, respectively. We have reported a switch from MAT1A to MAT2A gene expression in human liver cancer cells. In the current work, we examined whether the type of MAT expressed by the cell influences cell growth. HuH-7 cells were stably transfected with MAT1A and were subsequently treated with antisense oligonucleotides directed against MAT2A. MAT2A antisense treatment reduced the amount of MAT2A mRNA by 99% but had no effect on MAT1A mRNA. Cell growth and DNA synthesis rates were reduced by approximately 20-25% after transfection with MAT1A and by an additional 30-40% after MAT2A antisense treatment. SAM level and SAM:S-adenosylhomocysteine (SAH) ratio increased by 50-75% after MAT1A transfection and by an additional 60-80% after MAT2A antisense treatment. DNA methylation changed in parallel to changes in SAM level and SAM:SAH ratio. Supplementing untransfected HuH-7 cells with SAM in the culture medium increased SAM level, SAM:SAH ratio, and DNA methylation and decreased cell growth and DNA synthesis. In conclusion, cell growth is influenced by the type of MAT expressed. The mechanism likely involves changes in SAM:SAH ratio and DNA methylation.
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PMID:Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. 953 46

Liver-specific and non-liver-specific methionine adenosyltransferase (MAT) are products of two genes, MAT1A and MAT2A, respectively, that catalyze the formation of S-adenosylmethionine (SAM), the principal methyl donor. Mature liver expresses mainly MAT1A. We showed a switch from MAT1A to MAT2A gene expression in human liver cancer cells that may offer a growth advantage. To gain a better understanding of the chronology and significance of the change in MAT expression, we examined changes in hepatic MAT expression after acute treatment of rats with a hepatocarcinogen, thioacetamide (TAA). TAA treatment for 3 weeks did not change the MAT1A mRNA level but reduced the liver-specific MAT protein level to below 30% of control. TAA also acutely reduced the activity of liver-specific MAT when added to normal liver homogenates. In contrast, both the mRNA and protein levels of non-liver-specific MAT were induced. Because liver-specific MAT exhibits a much higher Km for methionine (mmol/L) than non-liver-specific MAT ( approximately 10 micromol/L), MAT activity was decreased at 5 mmol/L but increased at 20 micromol/L methionine concentration. The SAM level, SAM-to-S-adenosylhomocysteine (SAH) ratio, and DNA methylation all fell during treatment. In summary, TAA treatment induced differential changes in hepatic MAT expression. The reduction in liver-specific MAT protein level represents a novel mechanism of inactivation of liver-specific MAT. This along with induction in MAT2A contributed to a fall in the SAM-to-SAH ratio. The resulting DNA hypomethylation may be important in the process of hepatocarcinogenesis.
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PMID:Differential effect of thioacetamide on hepatic methionine adenosyltransferase expression in the rat. 1021 31

Methionine adenosyltransferase (MAT) is the enzyme that catalyzes the synthesis of S-adenosylmethionine (AdoMet), the main donor of methyl groups in the cell. In mammals MAT is the product of two genes, MAT1A and MAT2A. MAT1A is expressed only in the mature liver whereas fetal hepatocytes, extrahepatic tissues and liver cancer cells express MAT2A. The mechanisms behind the tissue and differentiation state specific MAT1A expression are not known. In the present work we examined MAT1A promoter methylation status by means of methylation sensitive restriction enzyme analysis. Our data indicate that MAT1A promoter is hypomethylated in liver and hypermethylated in kidney and fetal rat hepatocytes, indicating that this modification is tissue specific and developmentally regulated. Immunoprecipitation of mononucleosomes from liver and kidney tissues with antibodies mainly specific to acetylated histone H4 and subsequent Southern blot analysis with a MAT1A promoter probe demonstrated that MAT1A expression is linked to elevated levels of chromatin acetylation. Early changes in MAT1A methylation are already observed in the precancerous cirrhotic livers from rats, which show reduced MAT1A expression. Human hepatoma cell lines in which MAT1A is not expressed were also hypermethylated at this locus. Finally we demonstrate that MAT1A expression is reactivated in the human hepatoma cell line HepG2 treated with 5-aza-2'-deoxycytidine or the histone deacetylase inhibitor trichostatin, suggesting a role for DNA hypermethylation and histone deacetylation in MAT1A silencing.
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PMID:Liver-specific methionine adenosyltransferase MAT1A gene expression is associated with a specific pattern of promoter methylation and histone acetylation: implications for MAT1A silencing during transformation. 1062 84

Methionine adenosyltransferase (MAT) is an essential cellular enzyme which catalyses the formation of S-adenosylmethionine, the principal methyl donor and precursor for polyamines. In mammals, two different genes, MAT1A and MAT2A, encode for liver-specific and non-liver-specific MAT respectively. We previously described a switch in the MAT expression from MAT1A to MAT2A in human liver cancer, which offered the cancerous cell a growth advantage. Loss of MAT1A expression was due to lack of gene transcription. To study regulation of the MAT1A gene, we have cloned and characterized a 1.9 kb 5'-flanking region of the human MAT1A gene. One transcriptional start site, located 25 nt downstream from a consensus TATA box, was identified by primer extension and RNase protection assays. The promoter contains several consensus binding sites for CAAT enhancer binding protein (C/EBP) and hepatocyte-enriched nuclear factor (HNF), transcriptional factors important in liver-specific gene expression. The human MAT1A promoter was able to efficiently drive luciferase expression in Chang cells, a human liver cell line, but not in HeLa cells. Sequential deletion analysis of the promoter revealed two DNA regions upstream of the translational start site, -705 to -839 bp and -1111 to -1483 bp, which are involved in positive and negative gene regulation, respectively. Specific protein binding to these regions was confirmed by electrophoretic-mobility-shift and DNase I footprinting assays. Similar to the situation with the rat MAT1A, glucocorticoid treatment also increased human MAT1A expression and promoter activity in a dose- and time-dependent manner.
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PMID:Cloning and functional characterization of the 5'-flanking region of human methionine adenosyltransferase 1A gene. 1067 69

Methionine adenosyltransferase (MAT), an essential enzyme that catalyzes the formation of S-adenosylmethionine (SAM), is encoded by two genes, MAT1A (liver-specific) and MAT2A (non-liver-specific). We showed a switch from MAT1A to MAT2A expression in human liver cancer, which facilitates cancer cell growth. The present work examined the role of methylation in MAT2A transcriptional regulation. We found that the human MAT2A promoter is hypomethylated in hepatocellular carcinoma, in which the gene is upregulated transcriptionally, but hypermethylated in normal liver, in which the gene is minimally expressed. Luciferase activities driven by in vitro methylated MAT2A promoter constructs were 75-95% lower than activities driven by unmethylated constructs. SAM treatment of Hep G2 cells reduced MAT2A endogenous expression by 75%, hypermethylated the MAT2A promoter, and reduced luciferase activities driven by MAT2A promoter constructs by 65-75% while not affecting MAT1A's promoter activity. Treatment of adult rat and human hepatocytes with trichostatin A, an inhibitor of histone deacetylase, upregulated MAT2A expression by more than fourfold. Collectively, these results suggest that MAT2A expression is regulated by promoter methylation and histone acetylation.
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PMID:Role of promoter methylation in increased methionine adenosyltransferase 2A expression in human liver cancer. 1120 39

Two genes (MAT1A and MAT2A) encode for the essential enzyme methionine adenosyltransferase (MAT), which catalyzes the biosynthesis of S-adenosylmethionine (SAMe), the principal methyl donor and, in the liver, a precursor of glutathione. MAT1A is expressed mostly in the liver, whereas MAT2A is widely distributed. MAT2A is induced in the liver during periods of rapid growth and dedifferentiation. In human hepatocellular carcinoma (HCC) MAT1A is replaced by MAT2A. This is important pathogenetically because MAT2A expression is associated with lower SAMe levels and faster growth, whereas exogenous SAMe treatment inhibits growth. Rats fed ethanol intragastrically for 9 weeks also exhibit a relative switch in hepatic MAT expression, decreased SAMe levels, hypomethylation of c-myc, increased c-myc expression, and increased DNA strand break accumulation. Patients with alcoholic liver disease have decreased hepatic MAT activity owing to both decreased MAT1A expression and inactivation of the MAT1A-encoded isoenzymes, culminating in decreased SAMe biosynthesis. Consequences of chronic hepatic SAMe depletion have been examined in the MAT1A knockout mouse model. In this model, the liver is more susceptible to injury. In addition, spontaneous steatohepatitis develops by 8 months, and HCC develops by 18 months. Accumulating evidence shows that, in addition to being a methyl donor, SAMe controls hepatocyte growth response and death response. Whereas transient SAMe depletion is necessary for the liver to regenerate, chronic hepatic SAMe depletion may lead to malignant transformation. It is interesting that SAMe is antiapoptotic in normal hepatocytes, but proapoptotic in liver cancer cells. This should make SAMe an attractive agent for both chemoprevention and treatment of HCC.
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PMID:Role of methionine adenosyltransferase and S-adenosylmethionine in alcohol-associated liver cancer. 1605 84

S-adenosylmethionine arises as a central molecule in the preservation of liver homeostasis as a chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. In the present work, we have attempted a comprehensive analysis of proteins associated with hepatocarcinogenesis in MAT1A knock out mice using a combination of two-dimensional electrophoresis and mass spectrometry, to then apply the resulting information to identify hallmarks of human HCC. Our results suggest the existence of individual-specific factors that might condition the development of preneoplastic lesions. Proteomic analysis allowed the identification of 151 differential proteins in MAT1A-/- mice tumors. Among all differential proteins, 27 changed in at least 50% of the analyzed tumors, and some of these alterations were already detected months before the development of HCC in the KO liver. The expression level of genes coding for 13 of these proteins was markedly decreased in human HCC. Interestingly, seven of these genes were also found to be down-regulated in a pretumoral condition such as cirrhosis, while depletion of only one marker was assessed in less severe liver disorders.
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PMID:Molecular profiling of hepatocellular carcinoma in mice with a chronic deficiency of hepatic s-adenosylmethionine: relevance in human liver diseases. 1660 2

Hepatocyte growth factor (HGF) is a potent hepatocyte mitogen but its effect in liver cancer is conflicting. Methionine adenosyltransferase (MAT) is an essential enzyme encoded by two genes (MAT1A and MAT2A), while a third gene (MAT2beta) encodes for a subunit that regulates the MAT2A-encoded isoenzyme. MAT1A is silenced while MAT2A and MAT2beta are induced in hepatocellular carcinoma (HCC). The current work examined expression of HGF/c-met in HCC and whether HGF regulates MAT genes and growth in HepG2 cells. We found the mRNA levels of HGF and c-met are markedly increased in HCC. To study the influence of cell density, HepG2 cells were plated under high-density (HD) or low-density (LD) and treated with HGF (10 ng/ml). Cell density had a dramatic effect on MAT1A expression, being nearly undetectable at LD to a ninefold induction under HD. Cell density also determined the effect of HGF. At HD, HGF increased the mRNA levels of p21 and p27, while lowering the levels of MAT genes, cyclin A, and c-met. At LD, HGF increased the mRNA levels of cyclin A, MAT2A, MAT2beta, and c-met. Consistently, HGF inhibits growth under HD but stimulates growth under LD. HGF induced sustained high ERK activation under HD as compared to LD. In summary, HGF induces genes favoring growth and is mitogenic when HepG2 cells are plated under LD; however, the opposite occurs under HD. This involves cell density-dependent differences in HGF-induced ERK activation. This may explain why HGF is mitogenic only when there is loss of cell-cell contact in vivo.
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PMID:Effect of hepatocyte growth factor on methionine adenosyltransferase genes and growth is cell density-dependent in HepG2 cells. 1715 73

S-Adenosylmethionine (SAMe), the principal biological methyl donor, is synthesized from methionine and ATP in a reaction catalyzed by methionine adenosyltransferase (MAT). In mammals, two genes (MAT1A and MAT2A), encode for two homologous MAT catalytic subunits, while a third gene MAT2beta, encodes for the beta-subunit that regulates MAT2A-encoded isoenzyme. Normal liver expresses MAT1A, whereas extrahepatic tissues express MAT2A. MAT2A and MAT2 beta are induced in human hepatocellular carcinoma (HCC), which facilitate cancer cell growth. Patients with cirrhosis of various etiologies, including alcohol, have decreased hepatic MAT activity and SAMe biosynthesis. Consequences of hepatic SAMe deficiency as illustrated by the Mat1a knock-out mouse model include increased susceptibility to steatosis and oxidative liver injury, spontaneous development of steatohepatitis and HCC. Predisposition to HCC can be partly explained by the effect of SAMe on growth. Thus, SAMe inhibits the mitogenic effect of growth factors such as hepatocyte growth factor and, following partial hepatectomy, a fall in SAMe level is required for the liver to regenerate. During liver regeneration, the fall in hepatic SAMe is transient. If the fall were to persist, it would favor a proliferative phenotype and, ultimately, development of HCC. Not only does SAMe control liver growth, it also regulates apoptosis. Interestingly, SAMe is anti-apoptotic in normal hepatocytes but pro-apoptotic in liver cancer cells. In liver cancer cells but not in normal human hepatocytes, SAMe can selectively induce Bcl-x(S), an alternatively spliced isoform of Bcl-x(L) that promotes apoptosis. This should make SAMe an attractive agent for both chemoprevention and treatment of HCC.
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PMID:S-Adenosylmethionine in cell growth, apoptosis and liver cancer. 1833 69

SAMe (S-adenosylmethionine) is the main methyl donor group in the cell. MAT (methionine adenosyltransferase) is the unique enzyme responsible for the synthesis of SAMe from methionine and ATP, and SAMe is the common point between the three principal metabolic pathways: polyamines, transmethylation and transsulfuration that converge into the methionine cycle. SAMe is now also considered a key regulator of metabolism, proliferation, differentiation, apoptosis and cell death. Recent results show a new signalling pathway implicated in the proliferation of the hepatocyte, where AMPK (AMP-activated protein kinase) and HuR, modulated by SAMe, take place in HGF (hepatocyte growth factor)-mediated cell growth. Abnormalities in methionine metabolism occur in several animal models of alcoholic liver injury, and it is also altered in patients with liver disease. Both high and low levels of SAMe predispose to liver injury. In this regard, knockout mouse models have been developed for the enzymes responsible for SAMe synthesis and catabolism, MAT1A and GNMT (glycine N-methyltransferase) respectively. These knockout mice develop steatosis and HCC (hepatocellular carcinoma), and both models closely replicate the pathologies of human disease, which makes them extremely useful to elucidate the mechanism underlying liver disease. These new findings open a wide range of possibilities to discover novel targets for clinical applications.
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PMID:S-adenosylmethionine and proliferation: new pathways, new targets. 1879 49


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