Article

Phenotypic reversion of rat neoplastic liver nodules is under genetic control

Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
International Journal of Cancer (Impact Factor: 5.09). 05/2003; 105(1):70-5. DOI: 10.1002/ijc.11044
Source: PubMed

ABSTRACT

Low DNA synthesis and high redifferentiation (remodeling) characterize neoplastic nodules induced by chemical carcinogens in hybrid BFF1 rats, generated by crossing the susceptible F344 and resistant BN strains. We performed whole-genome scanning of BFF2 rats to identify loci controlling remodeling of nodules induced, 32 weeks after initiation with diethylnitrosamine, by the RH protocol. Remodeling nodules were identified as areas lacking uniformity of GST-P immunostaining and with irregular margins. Two loci in suggestive linkage with the percentage of remodeling nodules were identified on chromosomes 7 and 1 (LOD scores 3.85 and 2.9 at D7Rat25 and D1Mgh14). Significant dosage-negative effect of the B allele on remodeling and additive interaction between these loci were found. Significant epistatic interactions, showing a recessive, remodeling-enhancing effect of B alleles, occurred between D1Mit3 and D11Rat11 (corrected p = 0.0013) and between D6Rat14 and D8Rat46 (corrected p = 0.028). These data show that remodeling of neoplastic nodules during rat hepatocarcinogenesis is under genetic control. Loci affecting remodeling map to chromosomal regions syntenic to chromosomal segments of human HCC showing structural abnormalities.

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    • "Similar results were obtained for GGT transcription, indicating that phenotypic reversion might be controlled by factors operating at the levels of gene expression in both cases [57]. Recently, DeMiglio et al. [58] reported that remodeling of neoplastic nodules is under genetic control during chemical hepatocarcinogenesis in (BN x F344)F1 rats, that is, redifferentiation (remodeling ) of preneoplastic foci is linked with resistance to chemical carcinogenesis. The second change could then to be provided by a subsequent exposure to carcinogen, by exposure to a tumor-promoting agent, or by an indirect effect of the original exposure, suggesting epigenetic and genetic mechanisms could cooperate in malignant transformation . "
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    ABSTRACT: The expression of glutathione S-transferase P-form (GST-P) is markedly up-regulated in the initial phase of chemical hepatocarcinogenesis. It is unlikely that a specific genetic change is associated with this common response to a variety of carcinogens. Here, we describe how GST-P gene expression is induced by carcinogenic treatment, focusing on the changes in the network of liver-enriched transcription factors, including CCAAT/enhancer-binding proteins. Although the balance of positive and negative transcription factors regulates the expression of the GST-P gene, additional factors such as the altered regulation of growth control may certainly be necessary for these cells to develop into preneoplastic foci. Furthermore, our genetic analyses on the tumor susceptibility of (F344 x DRH)F2 rats support the hypothesis that the formation of GST-P-positive lesions is required but is not directly associated with final malignant transformation.
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    ABSTRACT: The expression of glutathione S-transferase P-form (GST-P) is markedly up-regulated in the initial phase of chemical hepatocarcinogenesis. It is unlikely that a specific genetic change is associated with this common response to a variety of carcinogens. Here, we describe how GST-P gene expression is induced by carcinogenic treatment, focusing on the changes in the network of liver-enriched transcription factors, including CCAAT/enhancer-binding proteins. Although the balance of positive and negative transcription factors regulates the expression of the GST-P gene, additional factors such as the altered regulation of growth control may certainly be necessary for these cells to develop into preneoplastic foci. Furthermore, our genetic analyses on the tumor susceptibility of (F344 x DRH)F2 rats support the hypothesis that the formation of GST-P-positive lesions is required but is not directly associated with final malignant transformation.
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