UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Down-regulation of GADD45beta, which is known to influence cell growth control, apoptosis, and cellular response to DNA damage, has been verified to be specific in hepatocellular carcinoma and consistent with the degree of malignancy. Here, we identified promoter elements for several transcriptional factors in the proximal promoter of GADD45beta using the luciferase assay. As a methyl donor for biological transmethylation reactions, S-adenosylmethionine (SAMe) could restore GADD45beta expression in HepG2 in Northern blot analyses and quantitative real-time polymerase chain reaction. Activity and binding capacity of nuclear factor (NF)-kappaB were confirmed to be specifically induced by SAMe, as evidenced by electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, and a decrease of IkappaBalpha in Western blot analyses. The most upstream NF-kappaB-binding site was crucial for transcriptional activation. In contrast to NF-kappaB, although there is an E2F-1-binding site adjacent to the NF-kappaB sites, treatment with SAMe could not induce E2F-1-binding activity. Despite showing a similar GADD45beta promoter regulatory pattern as HepG2 (p53 wild type), Hep3B (p53-null) did not exhibit GADD45beta induction by SAMe, and the induction could be partially recovered on reconstituting p53 in Hep3B. Thus, our results suggest that GADD45beta induction by SAMe via NF-kappaB may represent a novel mechanism of SAMe-mediated hepatoprotection, with p53 playing an important role.
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PMID:The induction of growth arrest DNA damage-inducible gene 45 beta in human hepatoma cell lines by S-adenosylmethionine. 1759 73

Hepatocellular carcinoma (HCC) is a highly malignant tumor, and chronic infection with hepatitis B virus is one of its major risk factors. To identify the proteins involved in HCC carcinogenesis, we used two-dimensional fluorescence DIGE to study the differentially expressed proteins in tumor and adjacent nontumor tissue samples. Samples from 12 hepatitis B virus-associated HCC patients were analyzed. A total of 61 spots were significantly up-regulated (ratio >/= 2, p </= 0.01) in tumor samples, whereas 158 spots were down-regulated (ratio </= -2, p </= 0.01). Seventy-one gene products were identified among these spots. Members of the heat shock protein 70 and 90 families were simultaneously up-regulated, whereas metabolism-associated proteins were decreased in HCC samples. The down-regulation of mitochondrial and peroxisomal proteins in these results suggested loss of special organelle functions during HCC carcinogenesis. Four metabolic enzymes involved in the methylation cycle in the liver were down-regulated in HCC tissues, indicating S-adenosylmethionine deficiency in HCC. Two gene products, glyceraldehyde-3-phosphate dehydrogenase and formimidoyltransferase-cyclodeaminase, were identified from inversely altered spots, suggesting that different isoforms or post-translational modifications of these two proteins might play different roles in HCC. For the first time, the overexpression of Hcp70/Hsp90-organizing protein and heterogeneous nuclear ribonucleoproteins C1/C2 in HCC tissues was confirmed by Western blot and then by immunohistochemistry staining in 70 HCC samples, suggesting their potential as protein tumor markers. In summary, we profiled proteome alterations in HCC tissues, and these results may provide useful insights for understanding the mechanism involved in the process of HCC carcinogenesis.
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PMID:Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues. 1762 33

MTAP (5'-methylthioadenosine phosphorylase) catalyses the reversible phosphorolytic cleavage of methylthioadenosine leading to the production of methylthioribose-1-phosphate and adenine. Deficient MTAP activity has been correlated with human diseases including cirrhosis and hepatocellular carcinoma. In the present study we have investigated the regulation of MTAP by ROS (reactive oxygen species). The results of the present study support the inactivation of MTAP in the liver of bacterial LPS (lipopolysaccharide)-challenged mice as well as in HepG2 cells after exposure to t-butyl hydroperoxide. Reversible inactivation of purified MTAP by hydrogen peroxide results from a reduction of V(max) and involves the specific oxidation of Cys(136) and Cys(223) thiols to sulfenic acid that may be further stabilized to sulfenyl amide intermediates. Additionally, we found that Cys(145) and Cys(211) were disulfide bonded upon hydrogen peroxide exposure. However, this modification is not relevant to the mediation of the loss of MTAP activity as assessed by site-directed mutagenesis. Regulation of MTAP by ROS might participate in the redox regulation of the methionine catabolic pathway in the liver. Reduced MTA (5'-deoxy-5'-methylthioadenosine)-degrading activity may compensate for the deficient production of the precursor S-adenosylmethionine, allowing maintenance of intracellular MTA levels that may be critical to ensure cellular adaptation to physiopathological conditions such as inflammation.
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PMID:Redox regulation of methylthioadenosine phosphorylase in liver cells: molecular mechanism and functional implications. 1823 76

There is clinical evidence that chronic liver diseases in which MDBs (Mallory Denk Bodies) form progress to hepatocellular carcinoma. The present study provides evidence that links MDB formation induced by chronic drug injury, with preneoplasia and later to the formation of tumors, which develop long after drug withdrawal. Evidence indicated that this link was due to an epigenetic cellular memory induced by chronic drug ingestion. Microarray analysis showed that the expressions of many markers of preneoplasia (UBD, Alpha Fetoprotein, KLF6 and glutathione-S-transferase mu2) were increased together when the drug DDC was refed. These changes were suppressed by S-adenosylmethionine feeding, indicating that the drug was affecting DNA and histones methylation in an epigenetic manner. The link between MDB formation and neoplasia formation was likely due to the over expression of UBD (also called FAT10), which is up regulated in 90% of human hepatocellular carcinomas. Immunohistochemical staining of drug-primed mouse livers showed that FAT10 positive liver cells persisted up to 4 months after drug withdrawal and they were still found in the livers of mice, 14 months after drug withdrawal. The refeeding of DDC increased the percent of FAT10 hepatocytes.
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PMID:Fat10 is an epigenetic marker for liver preneoplasia in a drug-primed mouse model of tumorigenesis. 1828 Apr 69

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in the Western population. By mechanisms that are not completely understood, this disease may progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). db/db mice spontaneously develop hepatic steatosis, which progresses to NASH when these mice are fed a methionine choline-deficient (MCD) diet. The goal of our studies was to identify lipid and methionine metabolism pathways affected by MCD feeding to determine potential causal events leading to the development of NASH from benign steatosis. db/db mice fed the MCD diet for 2 weeks exhibited signs of incipient NASH development such as upregulated cytokines and chemokines. At this time point, MCD diet feeding caused S-adenosylmethionine (SAMe) depletion in db/db mice, while wild-type mice on the same diet retained hepatic SAMe levels. SAMe depletion exerts pleiotropic effects upon liver homeostasis and is commonly associated with a variety of liver insults such as thioacetamide, CCL4, and alcohol treatment; thus, SAMe depletion may serve as the second hit in NASH development. It is possible that differences in hepatic lipid and/or methionine metabolism between wild-type and db/db mice underlay the differential maintenance of SAMe levels during methionine and choline restriction. Indeed, db/db mice exhibited inhibited lipid oxidation pathways, which may be a priming factor for NASH development, and db/db mice fed the MCD diet had differential methionine adenosyltransferase (MAT) expression. The occurrence of SAMe depletion at this early, benign stage of NASH development in db/db mice with fatty liver suggests that SAMe supplementation may be (A) targeted to individuals susceptible to NASH (i.e., NAFLD patients) and (B) preventative of NASH before substantial liver injury has occurred.
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PMID:The transition from fatty liver to NASH associates with SAMe depletion in db/db mice fed a methionine choline-deficient diet. 1829 81

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

Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine, the main methyl donor in cellular transmethylation reactions and the aminopropyl moiety in polyamine biosynthesis. In mammals, two different genes, MAT1A and MAT2A, encode catalytic polypeptides of liver-specific MAT I/III and ubiquitous MAT II, respectively. Reverse transcription-polymerase chain reaction showed that MAT1A gene expression was at a detectable level in embryonic day 14 mouse fetal liver and subsequently increased. Bisulfite genomic sequencing indicated that the methylation status of 10CpG sites in the MAT1A promoter proximal region was appreciably correlated with the gene expression in mouse developing liver and in adult hepatic cells; hepatic stellate cells and hepatocytes. When mouse hepatoma-derived Hepa-1 cells showing extremely low expression of MAT1A gene were treated with 5-aza-2'-deoxycytidine and trichostatin A, MAT1A gene expression was enhanced. In addition, in vitro methylation of the MAT1A promoter region suppressed the MAT1A promoter activity in reporter assay. Next, we performed electrophoretic mobility shift assay and found that the transcriptional factor CCAAT/enhancer binding protein-beta (C/EBPbeta) specifically binds to a putative binding site of C/EBPbeta in the MAT1A promoter. Suppression of C/EBPbeta expression by short hairpin RNA decreased the MAT1A promoter activity and MAT1A gene expression, and inhibition of C/EBPbeta binding to MAT1A by site-directed mutagenesis also showed similar results. Western blot analysis and chromatin immunoprecipitation assay indicated that C/EBPbeta binding is dependent on DNA methylation status. Based on these findings, we conclude that C/EBPbeta plays an important role in epigenetic regulation of the mature hepatic gene MAT1A.
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PMID:Involvement of CCAAT/enhancer binding protein-beta (C/EBPbeta) in epigenetic regulation of mouse methionine adenosyltransferase 1A gene expression. 1834 30

The DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) protects cells against the cytotoxic effects of alkylating agents. Therefore, modulation of MGMT expression in tumors is a possible strategy for improving the efficiency of cancer therapy. MGMT expression and activity is lost frequently in association with DNA hypermethylation of the MGMT promoter region. Since DNA and mRNA methylation are controlled by intracellular S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy) levels, we hypothesized a role for AdoMet/AdoHcy ratio in the regulation of MGMT promoter methylation and mRNA expression. Our initial studies showed that AdoMet/AdoHcy ratios vary over a wide range (7.0-50) in different glioblastoma and hepatoma cell lines. The studied cell lines exhibit distinct MGMT promoter methylation patterns: MGMT promoter was completely unmethylated in LN-18 and Tu 132 cells, hypermethylated in LN-229, U87-MG, and Tu 113 cells, and partially methylated in HepG2 cells. Furthermore, MGMT promoter methylation patterns and global DNA methylation are not related to intracellular AdoMet/AdoHcy ratio under control conditions. To lower AdoMet/AdoHcy ratio to values <1 we used AdoHcy hydrolase inhibitor adenosine-2',3'-dialdehyde (30 microM) and found that neither short-term (24 h) nor long-term changes (7 weeks) in AdoMet/AdoHcy ratio altered global or MGMT promoter methylation. However, experimentally elevated AdoHcy levels significantly decreased MGMT mRNA levels by >50% in all MGMT-expressing cell lines, which is most likely the result of impaired mRNA methylation. Thus, the present study suggests elevation of AdoHcy levels by AdoHcy hydrolase inhibition as a novel pharmacological approach to modulate MGMT expression and to increase the responsiveness to alkylating agents.
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PMID:Alterations in S-adenosylhomocysteine metabolism decrease O6-methylguanine DNA methyltransferase gene expression without affecting promoter methylation. 1839 86

Chronic hepatitis C virus (HCV) infection is a worldwide public health problem with a global prevalence of 2-3%. It is believed that about 170 million people are currently infected (about 3% of the world's population), and a further 3-4 million are infected each year. HCV is the main reason for liver transplantation in the developed world, and the main cause of liver-related morbidity and mortality in a number of countries, including Italy. It is not only a frequent cause of chronic liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma, but is also involved in the pathogenesis of various autoimmune and rheumatic disorders (arthritis, vasculitis, sicca syndrome, porphyria cutanea tarda, lichen planus, nephropathies, thyroid diseases, and lung fibrosis), as well as in the development of B-cell lymphoproliferative diseases. Furthermore, patients suffering from C hepatitis tend to produce rheumatoid factor, cryoglobulins and a large series of autoantibodies (ANA, anti-SSA/SSB, SAM, ATG, aCL). The use of glucocorticoids or immuno-suppressant agents in HCV infected individuals, which are needed to treat autoimmune and rheumatic disorders, leads to a risk of worsening the clinical outcome of HCV. Under these conditions, the viral infection often needs to be treated with antiviral agents, mainly pegylated interferon combined with ribavirin. However, cyclosporine A seems to be safe and effective in patients with autoimmune disease (AD) and concomitant chronic HCV infection as is documented by the reduction in viremia and transaminases, particularly in patients with high baseline levels. Finally, HCV is the main trigger of mixed cryoglobulinemia. An attempt at viral eradication is therefore indicated in most patients, and is particularly effective in the case of mild or moderate manifestations. In severe cases, rituximab is an apparently safe and effective alternative to conventional immunosuppression and, specifically, it controls B-cell proliferation.
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PMID:HCV infection: pathogenesis, clinical manifestations and therapy. 1857 Jul 53

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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