Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S-adenosylmethionine synthetase (SAMS) catalyzes the formation of S-adenosylmethionine (SAM) and is essential to normal cell function. There are two forms of SAMS, liver-specific and nonliver-specific (often referred to as "kidney"), which are products of two different genes. SAMS isoenzymes differ greatly in kinetic parameters and sensitivity to inhibition by methionine analogs. The current work studied changes in SAMS and their significance in liver cancer. Northern blot analysis showed that while normal liver expresses only liver-specific SAMS, both HepG2 and HuH-7 cells express only nonliver-specific SAMS. Absence of liver-specific SAMS messenger RNA (mRNA) was not because of gene deletion or rearrangement but complete lack of gene transcription. Reverse-transcription polymerase chain reaction (RT-PCR) with liver- and kidney-specific SAMS primers showed that liver-specific SAMS mRNA was absent with only kidney SAMS mRNA present in HepG2, HuH-7, Hep3B, and HuH-1 cells, and four consecutive hepatocellular carcinoma (HCC) specimens. Normal liver tissues from the same patients express both forms of SAMS mRNA. As a result of the change in SAMS expression, SAMS activity was higher in HepG2 and HuH-7 cells at physiologically relevant methionine concentrations but lower at high (mmol/L) methionine concentrations than rat hepatocytes. Treatment with ethionine and seleno-D,L-ethionine, two inhibitors known to have I50 values 50 to 60 times lower against SAMS purified from Novikoff hepatoma cells as compared with SAMS purified from normal rat liver, resulted in increased cell lysis in HepG2 and HuH-7 cells but not cultured rat hepatocytes. These agents did not affect cellular adenosine triphosphate (ATP) levels but inhibited SAMS activity in HepG2 and HuH-7 cells when added to their protein extracts. In summary, expression of SAMS is altered in human liver cancer. This occurrence may provide a potentially exploitable target for cancer chemotherapy.
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PMID:Changes in S-adenosylmethionine synthetase in human liver cancer: molecular characterization and significance. 890 81

An 18-month carcinogenicity study was conducted in male weanling F344 rats (28/group) to examine the effects of the simultaneous feeding of selected concentrations of ethionine and 0.05% phenobarbital in a normal chow diet. The effects of a 1-6-week feeding of phenobarbital and ethionine on the hepatic levels of the related metabolites S-adenosylmethionine, S-adenosylhomocysteine and S-adenosylethionine were also examined. Ethionine at 0.3% or 0.1% induced hepatocellular carcinoma (HCCa) at incidences of 90% (19/21) and 89% (24/27), respectively. Adding phenobarbital to the 0.1% ethionine diet reduced the incidence of HCCa to 36% (10/28) and reduced the number of liver tumor-associated deaths occurring prior to terminal sacrifice from 10/27 to 1/28. No hepatic tumors were observed in rats fed 0, 0.003, 0.01, or 0.03% ethionine. Phenobarbital alone or combined with 0.03% ethionine produced no hepatic tumors. Dietary ethionine at 0.1% reduced the intracellular hepatic level of S-adenosylmethionine to <50% of that seen in control rats. Phenobarbital alone had little effect on either S-adenosylmethionine or S-adenosylhomocysteine levels. The combination of phenobarbital and 0.1% ethionine led to increases in the hepatic levels of S-adenosylmethionine of 40-60% after 3 and 6 weeks of feeding, compared to those seen in rats receiving 0.1% ethionine alone. Ethionine feeding resulted in high levels of S-adenosylethionine in the livers. Combining phenobarbital with ethionine in the diet led to 30-50% reductions in hepatic S-adenosylethionine content. The results indicate that phenobarbital inhibits hepatocarcinogenesis by ethionine, that ethionine may cause HCCa via methyl group insufficiency, and that at levels of < or =0.03% ethionine did not show evidence of tumorigenicity.
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PMID:Suppression by phenobarbital of ethionine-induced hepatocellular carcinoma formation and hepatic S-adenosylethionine levels. 916 2

Mammalian S-adenosylmethionine (AdoMet) synthetase exists as two isozymes, liver-type and nonhepatic-type enzymes, which are the products of two different genes. It is known that the liver-type isozyme is only expressed in adult liver. Whereas, the nonhepatic-type isozyme is widely distributed in various tissues. In addition to the liver-type isozyme, a minor amount of the nonhepatic-type isozyme is also detected in adult liver. To investigate the distribution of these two isozymes in the liver in detail, the localization of these two isozymes was examined in each cell type of liver using a combination of cell fractionation technique and Western blot analysis. In the parenchymal cells, the liver-type isozyme protein was predominantly expressed, and a small amount of the nonhepatic-type isozyme protein was also detected. On the other hand, in the stellate cells the nonhepatic-type isozyme protein was exclusively or only expressed. Interestingly, a large amount of both isozymes were present in endothelial and Kupffer cell fraction. Using both antibodies to anti-rat nonhepatic-type and liver-type isozymes, respectively, immunohistochemical analysis clearly confirmed these results. In addition, in cultured hepatocellular carcinoma cells (FAA-HTC1), the nonhepatic-type isozyme protein only was detected, and the liver-type isozyme protein completely disappeared. This result indicates that the changes in the isozyme expression is regulated within the parenchymal cells. Administration of hepatotoxic drug carbon tetrachloride (CCl4) to rats resulted in about 40% to 50% reduction of enzyme activity in parenchymal cells and stellate cells compared with those of control rats. However, enzyme activity in endothelial and Kupffer cell fraction was not changed.
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PMID:Differential expression of S-adenosylmethionine synthetase isozymes in different cell types of rat liver. 925 54

Methionine adenosyltransferase is a ubiquitous enzyme that catalyzes the only known route of biosynthesis of S-adenosylmethionine, the major methyl group donor in cell metabolism. In mammals, two different methionine adenosyltransferases exist: one is confined to the liver, and the other one is distributed in extrahepatic tissues. In the present study, we report the cloning of the 5'-flanking region of liver-specific methionine adenosyltransferase gene from rat. Two closely spaced sites for transcriptional initiation were identified by primer extension analysis. The major transcription start site was determined to be 29 nucleotides downstream from the putative TATA box. Transient transfection assays of constructs containing sequentially deleted 5'-flanking sequences fused to the luciferase gene showed that rat hepatic methionine adenosyltransferase promoter was able to efficiently drive reporter expression not only in liver-type cells (rat hepatoma H35 cells and human hepatoblastoma HepG2 cells) but also in Chinese hamster ovary cells. Two regions spanning nucleotides -1251 to -958 and -197 to +65 were found to be crucial for the promoter efficiency. The distal upstream region contains elements that positively regulate promoter activity in H35 and HepG2 cells but are ineffective in Chinese hamster ovary cells. Eight protein binding sites were characterized in both regions by DNase I footprinting analysis. Two of these elements, sites A and B, located in the distal region, were found to be essential for the regulation of promoter activity. Electrophoretic mobility shift assays and competition experiments showed that site A is recognized by an NF1 protein. Site B was able to interact with a member of HNF-3 family when nuclear extracts from rat liver and H35 cells were used in the in vitro assay, but an additional binding activity to an NHF1-like protein was obtained with the hepatoma cell extracts. It is suggested that this differential binding can contribute to the cell specificity of promoter function.
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PMID:Characterization of rat liver-specific methionine adenosyltransferase gene promoter. Role of distal upstream cis-acting elements in the regulation of the transcriptional activity. 927 50

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

The glycine N-methyltransferase (GNMT) gene encodes a protein that not only acts as an enzyme to regulate the ratio of S-adenosylmethionine to S-adenosylhomocysteine, but also participates in the detoxification pathway in liver cells. Previously, we reported that the expression level of GNMT was diminished in human hepatocellular carcinoma. In this study, the human GNMT gene was cloned and characterized. It contains six exons and spans about 10 kb. Instead of a TATA box, it has a transcriptional initiator located 801 bp upstream from the translation start codon. The gene was localized to chromosome 6p12 using fluorescence in situ hybridization. Northern blot analysis of 16 tissues from different human organs showed that GNMT was expressed only in liver, pancreas, and prostate.
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PMID:Genomic structure, expression, and chromosomal localization of the human glycine N-methyltransferase gene. 1084 3

Methionine metabolism starts with the formation of S-adenosylmethionine (AdoMet), the most important biological methyl donor. This reaction is catalyzed by methionine adenosyltransferase (MAT). MAT is the product of two different genes: MAT1A, which is expressed only in the adult liver, and MAT2A, which is widely distributed, expressed in the fetal liver, and replaces MAT1A in hepatocarcinoma. In the liver, preservation of high expression of MAT1A and low expression of MAT2A is critical for the maintenance of a functional and differentiated organ. Here we describe that in cultured rat hepatocytes MAT1A expression progressively decreased, as described for other liver-specific genes, and MAT2A expression was induced. We find that this switch in gene expression was prevented by adding AdoMet to the culture medium. We also show that in cultured hepatocytes with decreased MAT1A expression AdoMet addition markedly increased MAT1A transcription in a dose-dependent fashion. This effect of AdoMet was mimicked by methionine, and blocked by 3-deazaadenosine and L-ethionine, but not D-ethionine, indicating that the effect was specific and mediated probably by a methylation reaction. These findings identify AdoMet as a key molecule that differentially regulates MAT1A and MAT2A expression and helps to maintain the differentiated status of the hepatocyte.
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PMID:S-adenosylmethionine regulates MAT1A and MAT2A gene expression in cultured rat hepatocytes: a new role for S-adenosylmethionine in the maintenance of the differentiated status of the liver. 1109 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

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of treatment. Therapy must include correction of nutritional deficiencies, while taking into account changes of nutritional requirements. Methionine is normally activated to S-adenosylmethionine (SAMe). However, in liver disease, the corresponding enzyme is depressed. The resulting deficiencies can be attenuated by the administration of SAMe but not by methionine. Similarly, phosphatidylethanolamine methyltransferase activity is depressed, but the lacking phosphatidylcholine (PC) can be administrated as polyenylphosphatidylcholine (PPC). Chronic ethanol consumption increases CYP2E1, resulting in increased generation of toxic acetaldehyde and free radicals, tolerance to ethanol and other drugs, and multiple ethanol-drug interactions. Experimentally, PPC opposes CYP2E1 induction and fibrosis. Alcoholism and hepatitis C infection commonly co-exist, with acceleration of fibrosis, cirrhosis, and hepatocellular carcinoma. PPC is being tested clinically as a corresponding antifibrotic agent. Available antiviral agents are contraindicated in the alcoholic. Anti-inflammatory agents, such as steroids, may be selectively useful. Finally, anticraving agents, such as naltrexone or acamprosate, should be part of therapy.
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PMID:Liver diseases by alcohol and hepatitis C: early detection and new insights in pathogenesis lead to improved treatment. 1126 19

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. We showed a switch from MAT1A to MAT2A expression at the transcriptional level in human hepatocellular carcinoma (HCC) that facilitates cancer cell growth. The purpose of the present study was to better understand the molecular mechanism of increased MAT2A expression in HCC. In vitro DNase I footprinting analysis revealed two protected sites (-354 to -312 and -73 to -28) using nuclear proteins from HCC and HepG2 cells, but not normal liver. These sites are also protected in HepG2 cells on in vivo DNase I footprinting analysis. These protected sites contain consensus binding sites for c-Myb and Sp1. In HCC, the mRNA levels of c-myb and Sp1 and binding to their respective sites increased. Mutation of the c-Myb or Sp1 site reduced MAT2A promoter activity by 67% and 50%, respectively. The importance of these cis-acting elements and trans-activating factors was confirmed using heterologous promoter and expression vectors. Increased expression of c-Myb and Sp1 and binding to the MAT2A promoter contribute to transcriptional up-regulation of MAT2A in HCC.-Yang, H., Huang, Z.-Z., Wang, J., Lu, S. C. The role of c-Myb and Sp1 in the up-regulation of methionine adenosyltransferase 2A gene expression in human hepatocellular carcinoma.
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PMID:The role of c-Myb and Sp1 in the up-regulation of methionine adenosyltransferase 2A gene expression in human hepatocellular carcinoma. 1142 82


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