The Choline-Devoid Diet Model of Hepatocarcinogenesis in the Rat

Lombardi, Benito

doi:10.1007/978-1-4757-9640-7_61

Cited by 11 publications

(2 citation statements)

References 71 publications

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“…Liver carcinogenesis can be divided into two types, depending on whether the inducing agent is an exogenous carcinogen or endogenous changes occurring without any established carcinogen exposure. The fact that unequivocal liver tumors can be induced by prolonged feeding of rats with a choline deficient (CD) diet is well known [9–11]. This can serve as the experimental model to assess possible mechanisms of endogenous carcinogenesis.…”

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confidence: 99%

CpG site hypermethylation of E‐cadherin and Connexin26 genes in hepatocellular carcinomas induced by a choline‐deficient L‐Amino Acid‐defined diet in rats

Tsujiuchi

Shimizu

Itsuzaki

et al. 2007

Molecular Carcinogenesis

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We investigated DNA methylation patterns of E-cadherin and Connexin26 (Cx26) genes in rat hepatocellular carcinomas (HCCs) induced by a choline-deficient L-Amino Acid-defined (CDAA) diet. Six-wks-old F344 male rats were continuously fed with a CDAA diet for 75 wks, and were then killed. A total of five HCCs were obtained, and genomic DNA was extracted from each HCC for assessment of methylation status in the 5' upstream regions of E-cadherin and Cx26 genes by bisulfite sequencing, comparing to two normal liver tissues. The five HCCs showed highly methylated E-cadherin and Cx26 genes, while these genes in two normal liver tissues were all unmethylated. For analysis of gene expression, real-time quantitative reverse transcription (RT)-polymerase chain reaction (PCR) was performed. Expressions of E-cadherin and Cx26 genes were significantly reduced in the five HCCs (P < 0.0001 and P < 0.001, respectively) compared to normal liver tissues, correlating with their methylation statuses. These results suggested that hypermethylation of E-cadherin and Cx26 genes may be involved in the development of HCCs induced by a CDAA diet in rats.

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Section: Introductionmentioning

confidence: 99%

CpG site hypermethylation of E‐cadherin and Connexin26 genes in hepatocellular carcinomas induced by a choline‐deficient L‐Amino Acid‐defined diet in rats

Tsujiuchi

Shimizu

Itsuzaki

et al. 2007

Molecular Carcinogenesis

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“…(1)(2)(3) The choline deficiency causes fatty liver, cirrhosis and HCC in rats. (1)(2)(3) Possible mechanisms underlying liver carcinogenesis from the CD diet have been proposed to include the following: liver necrosis associated with subsequent regeneration; (4,5) induction of oxidative DNA damage and lipid peroxidation; (6)(7)(8)(9) and generation of genetic alterations. (10,11) It has also been considered that DNA hypomethylation might play an important role in liver carcinogenesis induced by methyl donor deficiency.…”

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Disturbance of DNA methylation patterns in the early phase of hepatocarcinogenesis induced by a choline‐deficient L‐amino acid‐defined diet in rats

et al. 2007

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The authors investigated the DNA methylation patterns of the E-cadherin, Connexin 26 (Cx26), Rassf1a and c-fos genes in the early phase of rat hepatocarcinogenesis induced by a choline-deficient L-amino acid-defined (CDAA) diet. Six-week-old F344 male rats were continuously fed with the CDAA diet, and three animals were then killed at each of 4 and 8 days and 3 weeks. Genomic DNA was extracted from livers for assessment of methylation status in the 5′ ′ ′ ′ upstream regions of E-cadherin, Cx26, Rassf1a and c-fos genes by bisulfite sequencing, compared with normal livers. The livers of rats fed the CDAA diet for 4 and 8 days and 3 weeks were methylated in E-cadherin, Cx26 and Rassf1a genes, while normal livers were all unmethylated. In contrast, normal livers were highly methylated in c-fos gene. Although the livers at 4 days were weakly methylated, those at 8 days and 3 weeks were markedly unmethylated. Methylation patterns of CpG sites in E-cadherin, Cx26 and Rassf1a were sparse and the methylation was not associated with gene repression. These results indicate that gene-specific DNA methylation patterns were found in livers of rats after short-term feeding of the CDAA diet, suggesting gene-specific hypermethylation might be involved in the early phase of rat hepatocarcinogenesis induced by the CDAA diet. (Cancer Sci 2007; 98: 1318-1322) I t is well known that unequivocal liver tumors can be induced by prolonged feeding of rats with a CD diet.(1-3) The choline deficiency causes fatty liver, cirrhosis and HCC in rats.(1-3) Possible mechanisms underlying liver carcinogenesis from the CD diet have been proposed to include the following: liver necrosis associated with subsequent regeneration; (4,5) induction of oxidative DNA damage and lipid peroxidation; (6)(7)(8)(9) and generation of genetic alterations.(10,11) It has also been considered that DNA hypomethylation might play an important role in liver carcinogenesis induced by methyl donor deficiency.(12,13) So far, hypomethylation of the c-fos, c-myc, and c-Ha-ras genes has been detected in the livers of rats fed with the CD diet. (14,15) The CDAA diet used in the present study is semi-synthetic, and provides stronger carcinogenic effects than the CD diet in rats. (16,17) The authors have previously reported the hypomethylation of c-myc in HCC resulting from the CDAA diet in rats. (18) In another study, hypermethylation of the E-cadherin and Cx26 genes was also detected in those tumors.(19) While genomewide hypomethylation occurs in several human cancer cells, sitespecific hypermethylation such as CpG islands of tumor suppressor genes, is also found.(20) It has been suggested that aberrant DNA methylation of promoter regions of genes is the major mechanism of gene silencing in the development of tumors. (21,22) In fact, aberrant DNA methylation has been found in a variety of human cancers, including liver tumors. (23)(24)(25)(26) However, it is unclear why DNA hypermethylation occurs in rat HCC induced by the CDAA diet despite methyl donor deficiency. Therefore, ...

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Models for Liver Cancer

Feo

Pascale

Calvisi

2007

The Cancer Handbook

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Primary liver tumours include hepatocellular carcinomas (HCCs), cholangiocarcinomas, and hepatoblastomas. HCC is the most frequent liver tumour, whose development is preceded, both in humans and rodents, by the appearance in the liver of foci of altered hepatocytes (FAHs) and dysplastic nodules. Bipotential hepatic progenitor cells (HPCs), which may differentiate into hepatocytes or cholangiocytes, are liver tumour precursors. Several rodent models have been developed to study the aetiology, evolution, and pathogenesis of preneoplastic and neoplastic liver lesions. They include the woodchuck hepatitis model, chemical models in which hepatocyte initiation by a carcinogen is followed by a growth stimulus inducing clonal expansion of initiated cells, diet‐linked models based on induction of methyl donor deficiency, and transgenic/knockout models, particularly useful to study in vivo role(s) of genes favouring or suppressing neoplastic cell growth. Furthermore, in vitro growing liver tumour cell lines have been used to study the role of single genes or signal transduction pathways, the effect of inhibitor compounds and genome engineering on tumour growth, and gene expression profiles. Transplants of in vitro growing cells are currently used for chemopreventive and therapeutic approaches to hepatocarcinogenesis. Animal models of liver cancer allowed investigation of the molecular alterations involved in early stages and in the progression phase of hepatocarcinogenesis, thus evidencing the interspecies commonalties of the basic mechanisms of hepatocarcinogenesis, and strongly contributing to understanding the molecular bases of the disease. Finally, animal models allowed investigation of genetic predisposition to liver cancer and contributed to map predisposition genes, understanding the genetic model, and some effector mechanisms of cancer modifier genes.

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The Choline-Devoid Diet Model of Hepatocarcinogenesis in the Rat

Cited by 11 publications

References 71 publications

CpG site hypermethylation of E‐cadherin and Connexin26 genes in hepatocellular carcinomas induced by a choline‐deficient L‐Amino Acid‐defined diet in rats

CpG site hypermethylation of E‐cadherin and Connexin26 genes in hepatocellular carcinomas induced by a choline‐deficient L‐Amino Acid‐defined diet in rats

Disturbance of DNA methylation patterns in the early phase of hepatocarcinogenesis induced by a choline‐deficient L‐amino acid‐defined diet in rats

Models for Liver Cancer

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