Importance of a deficiency in S-adenosyl-l-methionine synthesis in the pathogenesis of liver injury,,,

Martínez‐Chantar, M. Luz; Garcı́a-Trevijano, Elena R.; Latasa, M Ujue; Pérez-Mato, Isabel; Pino, Manuel M. Sánchez del; Corrales, Fernando J.; Ávila, Matías A.; Mato, José M.

doi:10.1093/ajcn/76.5.1177s

Cited by 82 publications

(65 citation statements)

References 55 publications

(68 reference statements)

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“…[7][8][9][10][11][12][13][14]37 Knockout mice lacking Mat1A gene exhibit low hepatic levels of SAM, spontaneous oxidative stress, hepatic hyperplasia, steatohepatitis and HCC. 37 Furthermore, transfection of Hu-H7 cells with MAT1A and antisense oligonucleotides against MAT2A results in sizable decrease in DNA synthesis and increase in SAM level, SAM:SAH ratio, and DNA methylation.…”

Section: Discussionmentioning

confidence: 99%

“…12 Fall in MAT1A expression and MATI/III activity with concomitant upregulation of MAT2A occurs in hepatoma cell lines and rodent HCC as well as in human liver cirrhosis and HCC. 13,14 MATII isoform is inhibited by its reaction product and its upregulation does not lead to increase in SAM liver content. 12 Differential expression of MAT1A and Mat2A genes influences DNA methylation and growth of human HCC.…”

mentioning

confidence: 98%

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Altered methionine metabolism and global DNA methylation in liver cancer: Relationship with genomic instability and prognosis

Calvisi

Simile

Ladu

et al. 2007

Intl Journal of Cancer

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Mounting evidence underlines the role of genomic hypomethylation in the generation of genomic instability (GI) and tumorigenesis, but whether DNA hypomethylation is required for hepatocellular carcinoma (HCC) development and progression remains unclear. We investigated the correlation between GI and DNA methylation, and influence of methionine metabolism deregulation on these parameters and hepatocarcinogenesis in c-Myc and cMyc/Tgf-a transgenic mice and human HCCs. S-adenosyl-L-methionine/S-adenosylhomocysteine ratio and liver-specific methionine adenosyltransferase (MatI/III) progressively decreased in dysplastic and neoplastic liver lesions developed in c-Myc transgenic mice and in human HCC with better (HCCB) and poorer (HCCP) prognosis (based on patient's survival length). Deregulation of these parameters resulted in a rise of global DNA hypomethylation both in c-Myc and human liver lesions, positively correlated with GI levels in mice and humans, and inversely correlated with the length of survival of HCC patients. No changes in MATI/ III and DNA methylation occurred in c-Myc/Tgf-a lesions and in a small human HCC subgroup with intermediate prognosis, where a proliferative activity similar to that of c-Myc HCC and HCCB was associated with low apoptosis. Upregulation of genes involved in polyamine synthesis, methionine salvage and downregulation of polyamine negative regulator OAZ1, was highest in c-Myc/Tgf-a HCCs and HCCP. Our results indicate that alterations in the activity of MAT/I/III, and extent of DNA hypomethylation and GI are prognostic markers for human HCC. However, a small human HCC subgroup, as c-Myc/Tgf-a tumors, may develop in the absence of alterations in DNA methylation. ' 2007 Wiley-Liss, Inc.Key words: DNA hypomethylation; hepatocellular carcinoma; genomic instability; prognosis; transgenic mice Hepatocellular carcinoma (HCC), is the fifth most frequent human cancer, with the highest frequency in sub-Saharan Africa and far eastern Asia, where hepatitis B virus and hepatitis C virus infections are endemic and food is contaminated by Aflatoxin B1. 1 HCC incidence is rising in Europe and United States, presumably due to increased incidence of hepatitis C virus infection, cirrhosis related to Type II diabetes, and alcoholic hepatitis.2 HCC is rapidly fatal, since most patients at risk are not diagnosed in time and amenable to potentially curative treatments, i.e., partial liver resection or transplantation. 1,2 Hepatocarcinogenesis is characterized by the accumulation of various alterations in oncogenes and oncosuppressor genes.3 This event is presumably due to the increased tendency of initiated cells to acquire mutations following dysregulation of the mechanisms preserving genome integrity, a condition known as genomic instability 4 (GI). Indeed, a number of studies have demonstrated the progressive appearance of GI, such as point mutations, loss of heterozygosity and chromosomal alterations from preneoplastic liver to HCC.5 In addition, microsatellite instability occurs in HCC, although l...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

Altered methionine metabolism and global DNA methylation in liver cancer: Relationship with genomic instability and prognosis

Calvisi

Simile

Ladu

et al. 2007

Intl Journal of Cancer

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“…Mato's group demonstrated that knockout mice lacking this gene were predisposed to liver injury, exhibited increased expression of genes involved in cellular proliferation 158 , had impaired liver regeneration, had lower levels of SAMe, and spontaneously developed hepatocellular carcinomas 159,160 . S-nitrosylation of MAT I/III significantly decreased the levels of SAMe, and sensitized rat hepatocytes to enhanced proliferation 150,161,162 , which is mediated by hepatocyte growth factor scatter factor (HGF), and probably involves IGF-1 priming 163 . HGF is turned on by lower levels of SAMe 150 .…”

Section: S-nitrosylation Of Liver Methionine Adenosyltransferasementioning

confidence: 99%

Nitric Oxide and Cancer Development

et al. 2007

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Abstract:The role of nitric oxide (NO) in cancer development has become a very active research area. This review presents an overview of many studies that implicate an important role of NO in the development of cancer. These include results in experimental models as well as many observations made on NO and inducible nitric oxide synthase (iNOS) in human cancers. Our survey of the literature has allowed us to conclude that in general large levels of NO will kill cancer cells but paradoxically at intermediate to lower levels NO prevents cancer cell apoptosis and enhances tumor growth. This basic tenet has been demonstrated in many experimental models. The mechanistic basis of how intermediate levels of NO mediate tumor development is an active area of research and is the subject of this review. NO mediated S-nitrosylation of key enzymes and regulatory proteins plays a critical role. Key proteins S-nitrosylated which enhance tumor development include several caspases involved in apoptosis, PTEN the tumor suppressor protein, Bcl-2 the mitochondrial protein which protects from apoptosis, OGG1 the DNA repair protein and methionine adenosyl transferase the liver protein which synthesizes adenosylmethionine. The S-nitrosylation of these proteins enhances DNA mutations, prevents cancer cell apoptosis and enhances oncogenic cell growth. (J Toxicol Pathol 2007; 20: 77-92)

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“…MAT2A is hypomethylated in hepatocellular cancer and hypermethylated in normal liver supporting the above as a mechanism of methylation changes resulting in cancer promotion. 13,14 The reduced intake amongst alcoholics of key nutrients as well as the perturbation of enzymatic processes such as the production of SAMe by alcohol ingestion leads to further disturbance of important methylation reactions. One such example is the folate and methionine deficiency found in alcoholics which is associated with higher rates of colorectal cancer, an association that is not seen in occasional drinkers with replete levels of these nutritional factors.…”

Section: Alcohol Mediated Methylation Changesmentioning

confidence: 99%

DNA Methylation: Its Role in Cancer Development and Therapy

Kurkjian¹,

Kummar²,

Murgo³

2008

Current Problems in Cancer

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Inflammation and Methylation ChangesChanges in the genome which result in cancer promotion remain a complex interplay of aberrant methylation in the setting of a multitude of epigenetic changes. The events leading to these disruptions in methylation have been postulated; though remain to be fully elucidated. A causal relationship between inflammation and cancer has long been accepted in multiple tumor types, most prominently colon cancer; an association supported by the evidence that non-steroidal anti-inflammatory medications can potentially stop the development of colon cancer. Investigations in patients with ulcerative colitis who have a predisposition to the development of colon cancer have established a potential link between inflammation and cancer by the demonstration of hypermethylated gene promoters in early dysplastic lesions. 1 The mechanisms responsible for the contribution of inflammation to cancer remain to be fully understood. Mutagenesis resulting from the production of halogenated nucleotide precursors in activated neutrophils and eosinophils with subsequent incorporation into DNA has been demonstrated in vitro. 2,3 The link between inflammation-induced halogenated nucleotides and aberrant methylation stems from the demonstration that methyl-binding proteins cannot distinguish between methylated cytosine residues and chlorinated or brominated cytosine nucleotides. Furthermore, DNMT1 also could not distinguish between 5-methylcytosine and some 5-halocytosine products which could potentially result in mistaken methylation at sites of inflammation. 4 These halogenated cytosine residues were not recognized by DNA repair enzymes suggesting the possibility of accumulation of heritable changes within the genome.Infection with Helicobacter pylori has been implicated in the development of gastric cancer with a relative risk increase of 2.2-to 6 fold when infection is detected. 5-8 The mechanism of cancer development in this setting has been attributed to inflammation leading to cell proliferation resulting in a propensity for gene mutation. Aberrant methylation due to H. pylori infection has been suggested as an additional mechanism bridging the gap between inflammation and cancer. In a series of 154 healthy volunteers and 72 patients with gastric cancer, methylation of 8 regions of 7 CpG islands was assessed. 14 Among the healthy volunteers, the extent of DNA methylation was 5.4-to 303-times higher in the H. pylori positive cases compared to the H. pylori negative cases (p<0.0001) suggesting an increase in methylation levels due to the presence of H. pylori. However, the comparison of methylation levels between healthy volunteers and patients with gastric cancer stratified by H. pylori status

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Importance of a deficiency in S-adenosyl-l-methionine synthesis in the pathogenesis of liver injury,,,

Cited by 82 publications

References 55 publications

Altered methionine metabolism and global DNA methylation in liver cancer: Relationship with genomic instability and prognosis

Altered methionine metabolism and global DNA methylation in liver cancer: Relationship with genomic instability and prognosis

Nitric Oxide and Cancer Development

DNA Methylation: Its Role in Cancer Development and Therapy

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