Genetic properties for the suppression of development of putative preneoplastic glutathione S-transferase placental form-positive foci in the liver of carcinogen-resistant DRH strain rats

Denda, Ayumi; Kitayama, Wakashi; Konishi, Yoichi; Yan, Ying; Fukamachi, Yukiyo; Miura, Masayoshi; Gotoh, Sadao; Ikemura, Kunio; Abe, Tetsuya; Higashi, Taneaki; Higashi, Ken

doi:10.1016/s0304-3835(99)00051-8

Cited by 25 publications

(23 citation statements)

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“…2A). Previously we observed delayed appearance of the peak of DNA synthesis after partial hepatectomy in DRH/Sea rats relative to Crj:Donryu rats [3]. These results suggest that DRH/ Sea rats have intrinsic properties that differently regulate the response to some growth stimuli in vivo, although growth of DRH rats was similar to that of Crj:Donryu rats.…”

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confidence: 57%

“…in the livers of DRH/Sea and its parental Crj:Donryu rats [9]. Furthermore, comparable numbers of putatively preneoplastic glutathione S-transferase placental form (GST-P)-positive foci were detected after the SoltFarber protocol [7], but the area occupied by GST-P-positive lesions in the liver was much greater in Crj:Donryu rats than in DRH/Sea rats [3]. These observations suggested that clonal expansion of GST-P-positive foci was significantly suppressed in DRH/Sea rat livers.…”

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confidence: 95%

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Blunt Cell Growth Potential in Carcinogen Resistant Inbred DRH Rats.

et al. 2000

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A carcinogen-resistant inbred strain DRH/Sea has been developed from the Crj:Donryu strain. The rats had a very low incidence of liver tumors when they were fed diets containing a hepatocarcinogen such as 3'-methyl-4-dimethylamino-azobenzene (3'-Me-DAB). Despite using 3'-Me-DAB during the stage of selection, the DRH/Sea rats developed normally, reproduced and did not have any spontaneous tumor in the lung, liver or uterus at over 1 year of age. Although their growth curves were similar to the Crj:Donryu rats, the progression of polyploidization in the liver was significantly delayed when compared with Crj:Donryu rats. Mitogenic changes that occurred in the liver caused by either 3'-Me-DAB or lead nitrate were less significant in the DRH rats than in Crj:Donryu rats. Furthermore, the growth rate of cultured fibroblasts derived from the DRH rats was slower than that of Crj:Donryu rats. These results, together with our previous results, suggest that slow growth potential is present under certain conditions in DRH rats. These findings may explain partly the meaning of the different susceptibility to hepatocarcinogens. Key words: carcinogen-resistant rat, DRH/Sea, growth potential, ploidy but also in the uterus and via the milk. A pair of 12-week-old rats from the same litter were inbred and the rests were employed occasionally for the examination of either GGT-induction or hepatocarcinogenesis caused by 3'-Me-DAB. Therefore, many groups for inbreeding were maintained simultaneously, that is, more than 40 family lines on occasions. During this process, litters of rats that were premature at birth or grew poorly (Received 5 April 1999 / Accepted 8 July 1999 Corresponding address: K. Higashi, Department of Biochemistry, School of Medicine, University of Occupational and Environmental Health, Yahatanishiku, Japan Carcinogen-resistant rats were first isolated from Crj:Donryu rats (Charles River Japan, Inc.) based on examination of selective markers such as reduced induction of γ-glutamyltranspeptidase (GGT) and a very low incidence of liver tumors due to 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) [10,11]. Briefly, all the rats were exposed continuously to 3'-Me-DAB and its metabolites not only after weaning

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Blunt Cell Growth Potential in Carcinogen Resistant Inbred DRH Rats.

et al. 2000

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“…Genomic instability, up-regulation of oncogenes and downregulation of oncosuppressor genes, and in late stages, alteration of cell adhesion mechanisms drive the process evolution [15,21] . A striking behavior of rodents' genetic resistance to hepatocarcinogenesis is the fact that resistance genes apparently do not affect the initiation of the process, but only the capacity of initiated cells to grow autonomously [22][23][24][25] . In recent years the Brown norway (BN) [26] and Copenhag en (Cop) [27,28] rat strains have been shown to be strongly resistant to hepatocarcinogenesis.…”

Section: Resistant Phenotypementioning

confidence: 99%

Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

Feo¹,

Frau²,

Pascale³

2008

WJG

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Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma (HCC). Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway (BN) rats. Unrestrained extracellular signal-regulated kinase (ERK) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (DUSP1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-kB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-α transgenic mice. iNOS, IKK/NF-kB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.

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“…According to the concept of multistage carcinogenesis, clones of cells arise with increasing autonomy from normal growth regulation at each stage of development, and from these selected populations of cells, neoplasms ultimately develop [4] . The placental form of rat glutathione S-transferase (rGST P) positive foci is thought to be preneoplastic lesions of the liver [5][6][7][8][9][10][11][12] . Peroxisome proliferators-activated receptor γ (PPARγ), a nuclear hormone receptor, provides a strong link between lipid metabolism and regulation of gene transcription.…”

Section: Introductionmentioning

confidence: 99%