Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas

Alteration of DNA methylation is one of the most consistent epigenetic changes in human cancers. DNA methyltransferase (DNMT) 1 is a major enzyme involved in establishing genomic methylation patterns. Most of the studies concerning DNMT1 expression in human cancers have been performed only at the mRNA level. To directly examine DNMT1 protein expression levels during human hepatocarcinogenesis, 16 histologically normal liver tissues, 51 noncancerous liver tissues exhibiting chronic hepatitis or cirrhosis, which are considered to be precancerous conditions, and 53 hepatocellular carcinomas (HCCs) were subjected to immunohistochemic examination. If more than 20% of the cells exhibited nuclear DNMT1 staining, the tissue sample was considered to be DNMT1‐positive. DNMT1 immunoreactivity was observed in 23 (43%) of the HCCs, but in none (0%) of the histologically normal liver or noncancerous liver tissues exhibiting chronic hepatitis or cirrhosis. The incidence of increased DNMT1 protein expression in HCCs correlated significantly with poor tumor differentiation (p = 0.0006) and portal vein involvement (p = 0.0002). Moreover, the recurrence‐free (p = 0.0001) and overall (p < 0.0001) survival rates of patients with HCCs exhibiting increased DNMT1 protein expression were significantly lower than those of patients with HCCs that did not exhibit increased expression. Increased DNMT1 protein expression may play a critical role in the malignant progression of HCCs and be a biologic predictor of both HCC recurrence and a poor prognosis in HCC patients. © 2003 Wiley‐Liss, Inc.

[1]  K. Robertson.  DNA methylation and chromatin – unraveling the tangled web , 2002, Oncogene.

[2]  S. Hirohashi,et al.  Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[4]  Bert Vogelstein,et al.  DNMT1 and DNMT3b cooperate to silence genes in human cancer cells , 2002, Nature.

[5]  Gangning Liang,et al.  Cooperativity between DNA Methyltransferases in the Maintenance Methylation of Repetitive Elements , 2002, Molecular and Cellular Biology.

[6]  R. Dahiya,et al.  Histone deacetylase and DNA methyltransferase in human prostate cancer. , 2001, Biochemical and biophysical research communications.

[7]  Keith D Robertson,et al.  DNA methylation, methyltransferases, and cancer , 2001, Oncogene.

[8]  J. Herman,et al.  Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. , 2001, Human molecular genetics.

[9]  H Ishii,et al.  Expression of mRNA for DNA methyltransferases and methyl‐CpG–binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis , 2001, Hepatology.

[10]  S. Hirohashi,et al.  Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis—A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma , 2000, Hepatology.

[11]  Peter L. Jones,et al.  DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters , 2000, Nature Genetics.

[12]  S. Hirohashi,et al.  Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis. , 2000, Cancer letters.

[13]  Luke Hughes-Davies,et al.  DNA methyltransferase Dnmt1 associates with histone deacetylase activity , 2000, Nature Genetics.

[14]  A. Marzo,et al.  Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis. , 1999, Cancer research.

[15]  S. Hirohashi,et al.  DNA hypermethylation at the D17S5 locus and reduced HIC‐1mRNA expression are associated with hepatocarcinogenesis , 1999, Hepatology.

[16]  Rudolf Jaenisch,et al.  DNA hypomethylation leads to elevated mutation rates , 1998, Nature.

[17]  E. Li,et al.  Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases , 1998, Nature Genetics.

[18]  S. Hirohashi,et al.  DNA hypermethylation at the D17S5 locus is associated with gastric carcinogenesis. , 1998, Cancer letters.

[19]  S. Hirohashi,et al.  Increased DNA Methyltransferase Expression Is Associated with an Early Stage of Human Hepatocarcinogenesis , 1997, Japanese journal of cancer research : Gann.

[20]  S. Hirohashi,et al.  DNA hypermethylation at the D17S5 locus in non-small cell lung cancers: its association with smoking history. , 1997, Cancer research.

[21]  H. Ng,et al.  Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. , 1997, Science.

[22]  S. Baylin.  Tying It All Together: Epigenetics, Genetics, Cell Cycle, and Cancer , 1997, Science.

[23]  S. Hirohashi,et al.  The E‐cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas , 1997, International journal of cancer.

[24]  S. Hirohashi,et al.  Reduced p21WAF1/CIP1 expression and p53 mutation in hepatocellular carcinomas , 1997, Hepatology.

[25]  S. Hirohashi,et al.  Aberrant DNA Methylation on Chromosome 16 Is an Early Event in Hepatocarcinogenesis , 1996, Japanese journal of cancer research : Gann.

[26]  S. Baylin,et al.  De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase , 1996, Molecular and cellular biology.

[27]  S. Hirohashi,et al.  Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[28]  H. Novotná,et al.  Hypomethylation of CCGG sites in the 3' region of H-ras protooncogene is frequent and is associated with H-ras allele loss in non-small cell lung cancer. , 1994, Cancer research.

[29]  S. Baylin,et al.  Regional DNA hypermethylation at D17S5 precedes 17p structural changes in the progression of renal tumors. , 1993, Cancer research.

[30]  Peter A. Jones,et al.  High frequency mutagenesis by a DNA methyltransferase , 1992, Cell.

[31]  O. Hino,et al.  Clonal growth of hepatitis B virus-integrated hepatocytes in cirrhotic liver nodules. , 1992, Cancer research.

[32]  H. Leonhardt,et al.  A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei , 1992, Cell.

[33]  T. Bestor,et al.  Activation of mammalian DNA methyltransferase by cleavage of a Zn binding regulatory domain. , 1992, The EMBO journal.

[34]  H. Hasegawa,et al.  Clonal origin of atypical adenomatous hyperplasia of the liver and clonal identity with hepatocellular carcinoma. , 1988, Gastroenterology.

[35]  V. Ingram,et al.  Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. , 1988, Journal of molecular biology.

[36]  M. Kojiro,et al.  A NEW HUMAN PLEOMORPHIC HEPATOCELLULAR CARCINOMA CELL LINE, KYN‐2 , 1988, Acta pathologica japonica.

[37]  M. Ehrlich,et al.  The 5-methylcytosine content of DNA from human tumors. , 1983, Nucleic acids research.

[38]  C C Howe,et al.  Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. , 1980, Science.