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

被引：65

作者：

Calvisi, Diego F. ^{[1
]}

Simile, Maria M. ^{[1
]}

Ladu, Sara ^{[1
]}

Pellegrino, Rossella ^{[1
]}

De Murtas, Valentina ^{[1
]}

Pinna, Federico ^{[1
]}

Tomasi, Maria L. ^{[1
]}

Fran, Maddalena ^{[1
]}

Virdis, Patrizia ^{[1
]}

De Miglio, Maria R. ^{[1
]}

Muroni, Maria R. ^{[1
]}

Pascale, Rosa M. ^{[1
]}

Feo, Francesco ^{[1
]}

机构：

[1] Univ Sassari, Sect Patol Sperimentale, Dipartimento Sci Biomed, Div Expt Pathol & Oncol, I-07100 Sassari, Italy

来源：

INTERNATIONAL JOURNAL OF CANCER | 2007年 / 121卷 / 11期

关键词：

DNA hypomethylation; hepatocellular carcinoma; genomic instability; prognosis; transgenic mice;

D O I：

10.1002/ijc.22940

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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/Tgf-alpha 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-alpha 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-alpha 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. (C) 2007 Wiley-Liss, Inc.

引用

页码：2410 / 2420

页数：11

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