• 1
    Feitelson MA, Sun B, Satiroglu Tufan NL, Liu J, Pan J, Lian Z. Genetic mechanisms of hepatocarcinogenesis. Oncogene 2000; 221: 2593604.
  • 2
    Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004; 127: S5S16.
  • 3
    Feo F, Pascale RM, Simile MM, De Miglio MR, Muroni MR, Calvisi DF. Genetic alterations in liver carcinogenesis. Crit Rev Oncog 2000; 11: 1962.
  • 4
    Loeb LA, Loeb KR, Anderson JP. Multiple mutations and cancer. Proc Natl Acad Sci USA 2003; 100: 77681.
  • 5
    Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002; 31: 33946.
  • 6
    Ghoshal AK, Farber E. The induction of liver cancer by dietary deficiency of choline and methionine without added carcinogens. Carcinogenesis 1984; 5: 136770.
  • 7
    Wainfan E, Poirier LA. Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. Cancer Res 1992; 52: 2071s77s.
  • 8
    Garcea R, Daino L, Pascale RM, Simile MM, Puddu M, Ruggiu ME, Seddaiu MA, Satta G, Sequenza MJ, Feo F. Protooncogene methylation and expression in regenerating liver and preneoplastic liver nodules induced in the rat by diethylnitrosamine: effect of variations of S-adenosylmethionine:S-adenosylhomocysteine ratio. Carcinogenesis 1989; 10: 118392.
  • 9
    Garcea R, Daino L, Pascale RM, Simile MM, Puddu M, Frassetto S, Cozzolino P, Seddaiu MA, Gaspa L, Feo F. Inhibition of promotion and persistent nodule growth by S-adenosyl-L-methionine in rat liver carcinogenesis: role of remodeling and apoptosis. Cancer Res 1989; 49: 18506.
  • 10
    Pascale RM, Marras V, Simile MM, Daino L, Pinna G, Bennati S, Carta M, Seddaiu MA, Massarelli G, Feo F. Chemoprevention of rat liver carcinogenesis by S-adenosyl-L-methionine: a long-term study. Cancer Res 1992; 52: 497986.
  • 11
    Avila MA, Berasain C, Torres L, Martin-Duce A, Corrales FJ, Yang H, Prieto J, Lu SC, Caballeria J, Rodes J, Mato JM. Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol 2000; 33: 90714.
  • 12
    Mato JM, Corrales FJ, Lu SC, Avila MA. S-Adenosylmethionine: a control switch that regulates liver function. FASEB J 2002; 16: 1526.
  • 13
    Cai J, Sun WM, Hwang JJ, Stain SC, Lu SC. Changes in S-adenosylmethionine synthetase in human liver cancer: molecular characterization and significance. Hepatology 1996; 24: 10907.
  • 14
    Martínez-Chantar ML, García-Trevijano ER, Latasa MU, Perez-Mato I, Sanchez del Pino MM, Corrales FJ, Avila MA, Mato JM. Importance of a deficiency in S-adenosyl-L-methionine synthesis in the pathogenesis of liver injury. Am J Clin Nutr 2002; 76: 1177S82S.
  • 15
    Cai J, Mao Z, Hwang JJ, Lu SC. Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. Cancer Res 1998; 58: 144450.
  • 16
    Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 2003; 300: 455.
  • 17
    Rodriguez J, Frigola J, Vendrell E, Risques RA, Fraqa MF, Morales C, Moreno V, Esteller M, Capellá G, Ribas M, Peinado MA. Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res 2006; 66: 84628.
  • 18
    Kokalj-Vokac N, Almeida A, Viegas-Pequignot E, Jeanpierre M, Malfoy B, Dutrillaux B. Specific induction of uncoiling and recombination by azacytidine in classical satellite-containing constitutive heterochromatin. Cytogenet Cell Genet 1993; 63: 1115.
  • 19
    Ji W, Hernandez R, Zhang XY, Qu GZ, Frady A, Varela M, Ehrlich M. DNA demethylation and pericentromeric rearrangements of chromosome 1. Mutat Res 1997; 379: 3341.
  • 20
    James SJ, Pogribny IP, Pogribna M, Mille BJ, Jernigan S, Melnyk S. Mechanisms of DNA damage, DNA hypomethylation, and tumor progression in the folate/methyl-deficient rat model of hepatocarcinogenesis. J Nutr 2003; 133: 3740S7S.
  • 21
    Yamada Y, Jackson-Grusby L, Linhart H, Linhart H, Meissner A, Eden A, Lin H, Jaenisch R. Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc Natl Acad Sci USA 2005; 102: 135805.
  • 22
    Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H, Jaenisch R. Induction of tumors in mice by genomic hypomethylation. Science 2003; 300: 48992.
  • 23
    Pascale RM, Simile MM, Ruggiu ME, Seddaiu MA, Satta G, Sequenza MJ, Daino L, Vannini MG, Lai P, Feo F. Reversal by 5-azacytidine of the S-adenosyl-L-methionine-induced inhibition of the development of putative preneoplastic foci in rat liver carcinogenesis. Cancer Lett 1991; 56: 25965.
  • 24
    Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, Monges G, Thomas G, Bioulac-Sage P, Zucman-Rossi J. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology 2001; 120: 176373.
  • 25
    Lee JS, Chu IS, Mikaelyan A, Calvisi DF, Heo J, Reddy JK, Thorgeirsson SS. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 2004; 36: 130611.
  • 26
    Murakami H, Sanderson ND, Nagy P, Marino PA, Merlino G, Thorgeirsson SS. Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor alpha in hepatic oncogenesis. Cancer Res 1993; 53: 171923.
  • 27
    Pascale RM, Simile MM, Calvisi DF, Frau M, Muroni MR, Seddaiu MA, Daino L, Muntoni MD, De Miglio MR, Thorgeirsson SS, Feo F. Role of HSP90, CDC37, and CRM1 as modulators of P16(INK4A) activity in rat liver carcinogenesis and human liver cancer. Hepatology 2005; 42: 13109.
  • 28
    Kramer DL, Sufrin JR, Porter CW. Relative effects of S-adenosylmethionine depletion on nucleic acid methylation and polyamine biosynthesis. Biochem J 1987; 247: 25965.
  • 29
    Simile MM, Banni S, Angioni E, Carta G, De Miglio MR, Muroni MR, Calvisi DF, Carru A, Pascale RM, Feo F. 5′-Methylthioadenosine administration prevents lipid peroxidation and fibrogenesis induced in rat liver by carbon-tetrachloride intoxication. J Hepatol 2001; 34: 38694.
  • 30
    Santoni-Rugiu E, Jensen MR, Thorgeirsson SS. Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor alpha Cancer Res 1998; 58: 12334.
  • 31
    Pogribny I, Yi P, James SJ. Sensitive new method for rapid detection of abnormal methylation patterns in global DNA and within CpG islands. Biochem Biophys Res Commun 1999; 262: 6248.
  • 32
    Balaghi M, Wagner C. DNA methylation in folate deficiency: use of CpG methylase. Biochem Biophys Res Commun 1993; 193: 118490.
  • 33
    Woodward SR, Sudweeks J, Teuscher C. Random sequence oligonucleotide primers detect polymorphic DNA products which segregate in inbred strains of mice. Mamm Genome 1992; 3: 738.
  • 34
    Luceri C, De Filippo C, Caderni G, Gambacciani L, Salvadori M, Giannini A, Dolara P. Detection of somatic DNA alterations in azoxymethane-induced F344 rat colon tumors by random amplified polymorphic DNA analysis. Carcinogenesis 2000; 21: 17536.
  • 35
    Atienzar FA, Jha AN. The random amplified polymorphic DNA (RAPD) assay and related techniques applied to genotoxicity and carcinogenesis studies: a critical review. Mutat Res 2006; 613: 76102.
  • 36
    Calvisi DF, Thorgeirsson SS. Molecular mechanisms of hepatocarcinogenesis in transgenic mouse models of liver cancer. Toxicol Pathol 2005; 33: 1814.
  • 37
    Martínez-Chantar ML, Corrales FJ, Martínez-Cruz LA, Garcia-Trevijano ER, Huang ZZ, Chen L, Kanel G, Avila MA, Mato JM, Lu SC. Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. FASEB J 2002; 16: 12924.
  • 38
    Widschwendter M, Jiang G, Woods C, Muller HM, Fiegl H, Goebel G, Marth C, Muller-Holzner E, Zeimet AG, Laird PW, Ehrlich M. DNA hypomethylation and ovarian cancer biology. Cancer Res 2004; 64: 447280.
  • 39
    Piyathilake CJ, Henao O, Frost AR, Macaluso M, Bell WC, Johanning GL, Heimburger DC, Niveleau A, Grizzle WE. Race- and age-dependent alterations in global methylation of DNA in squamous cell carcinoma of the lung. J Cancer Causes Control 2003; 14: 3742.
  • 40
    Soares J, Pinto AE, Cunha CV, Andre S, Barao I, Sousa JM, Cravo M. Global DNA hypomethylation in breast carcinoma. Correlation with prognostic factors and tumor progression. Cancer 1999; 85: 1128.
  • 41
    Bernardino J, Roux C, Almeida A, Vogt N, Gibaud A, Gerbault-Seureau M, Magdelenat H, Bourgeois CA, Malfoy B, Dutrillaux B. DNA hypomethylation in breast cancer: an independent parameter of tumor progression? Cancer Genet Cytogenet 1997; 97: 839.
  • 42
    Hermes M, Osswald H, Kloor D. Role of S-adenosylhomocysteine hydrolase in adenosine-induced apoptosis in HepG2 cells. Exp Cell Res 2007; 313: 26483.
  • 43
    Factor VM, Laskowska D, Jensen MR, Woitach JT, Popescu NC, Thorgeirsson SS. Vitamin E reduces chromosomal damage and inhibits hepatic tumor formation in a transgenic mouse model. Proc Natl Acad Sci USA 2000; 97: 2196201.
  • 44
    Calvisi DF, Ladu S, Hironaka K, Factor VM, Thorgeirsson SS. Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-alpha transgenic mouse model of liver cancer. J Hepatol 2004; 41: 81522.
  • 45
    Ikeguchi M, Ueta T, Yamane Y, Hirooka Y, Kaibara N. Inducible nitric oxide synthase and survivin messenger RNA expression in hepatocellular carcinoma. Clin Cancer Res 2002; 8: 31316.
  • 46
    Torres L, Avila MA, Carretero MV, Latasa MU, Caballeria J, Lopez-Rodas G, Boukaba A, Lu SC, Franco L, Mato JM. 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. FASEB J 2000; 14: 95102.
  • 47
    Laird PW, Jackson-Grusby L, Fazeli A, Dickinson SL, Jung WE, Li E, Weinberg RA, Jaenisch R. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 1995; 81: 197205.
  • 48
    Cormier RT, Dove WF. Dnmt1N/+ reduces the net growth rate and multiplicity of intestinal adenomas in C57BL/6-multiple intestinal neoplasia (Min)/+ mice independently of p53 but demonstrates strong synergy with the modifier of Min 1(AKR) resistance allele. Cancer Res 2000; 60: 396570.
  • 49
    Eads CA, Nickel AE, Laird PW. Complete genetic suppression of polyp formation and reduction of CpG-island hypermethylation in Apc(Min/+) Dnmt1-hypomorphic Mice. Cancer Res 2002; 62: 12969.