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首页> 外文期刊>Molecular Carcinogenesis >Sequential changes in hepatocarcinogenesis induced by diethylnitrosamine plus thioacetamide in Fischer 344 rats: induction of gankyrin expression in liver fibrosis, pRB degradation in cirrhosis, and methylation of p16(INK4A) exon 1 in hepatocellular
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Sequential changes in hepatocarcinogenesis induced by diethylnitrosamine plus thioacetamide in Fischer 344 rats: induction of gankyrin expression in liver fibrosis, pRB degradation in cirrhosis, and methylation of p16(INK4A) exon 1 in hepatocellular

机译：二乙基亚硝胺加硫代乙酰胺在费雪344大鼠中引起肝癌的顺序变化：肝纤维化中gankyrin表达的诱导，肝硬化中pRB的降解以及肝细胞中p16（INK4A）外显子1的甲基化

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To clarify the sequential changes in pRB and p16 during different stages of hepatocarcinogenesis such as fibrosis, cirrhosis, hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC), male Fischer 344 rats were singly injected with diethylnitrosamine (DEN), immediately followed with phenobarbital for 1 wk and then thioacetamide (TAA) for 39 wk in drinking water. Rats were killed at 9, 20, 30, and 40 wk after DEN initiation and changes of pRB level, p16 gene hypermethylation, and in vivo gankyrin expression were examined. Histologic examination showed stepwise appearances of fibrosis, cirrhosis, HCA, and HCC at weeks 9, 20, 30, and 40, respectively. Hypermethylation of p16 exon 1 was not found until HCA but appeared in 50% of the rats with HCC accompanied by complete loss of its mRNA expression. The amount of glutathione S-transferase--gankyrin bound to pRB and pRB degradation in the liver depended on the concentration of gankyrin and incubation time. Gankyrin expression preceded pRB degradation in liver cirrhosis. In conclusion, gankyrin expression induced in liver fibrosis accelerated the degradation of pRB during liver cirrhosis, and inactivation of p16 exon 1 by DNA hypermethylation occurred during the progression of tumor cells to poorly differentiated HCC. Inactivation of pRB and/or p16 resulted in complete loss of regulation in the cell-division cycle during early and late stages, respectively, of hepatocarcinogenesis. Mol. Carcinog. 30:138--150, 2001. Copyright 2001 Wiley-Liss, Inc.
机译：为了阐明在肝癌发生的不同阶段（例如纤维化，肝硬化，肝细胞腺瘤（HCA）和肝细胞癌（HCC））中pRB和p16的顺序变化，对雄性Fischer 344大鼠分别注射了二乙基亚硝胺（DEN），并立即注射苯巴比妥1周，然后在饮用水中加入39周的硫代乙酰胺（TAA）。 DEN引发后第9、20、30和40周处死大鼠，并检查pRB水平，p16基因高甲基化和体内gankyrin表达的变化。组织学检查显示在第9、20、30和40周分别出现纤维化，肝硬化，HCA和HCC的逐步出现。直到HCA才发现p16外显子1的超甲基化，但在50％的HCC大鼠中出现，同时其mRNA表达完全丧失。肝脏中与pRB和pRB降解结合的谷胱甘肽S-转移酶-gankyrin的量取决于gankyrin的浓度和孵育时间。肝硬化中，gankyrin表达先于pRB降解。总之，肝纤维化中诱导的gankyrin表达加速了肝硬化过程中pRB的降解，并且在肿瘤细胞向低分化肝癌进展期间，DNA高甲基化导致p16外显子1失活。 pRB和/或p16的失活分别在肝癌发生的早期和晚期分别导致细胞分裂周期的调控完全丧失。大声笑Carcinog。 30：138--150，2001.版权所有2001 Wiley-Liss，Inc.

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