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首页> 外文期刊>Experimental Animals >Aurora-A Overexpression in Mouse Liver Leads to a Low Incidence of Hepatic Tumors and Causes p53-dependent G2/M Arrest during Liver Regeneration
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Aurora-A Overexpression in Mouse Liver Leads to a Low Incidence of Hepatic Tumors and Causes p53-dependent G2/M Arrest during Liver Regeneration

机译：小鼠肝脏中的Aurora-A过表达导致肝肿瘤的低发生率，并在肝脏再生过程中引起p53依赖性G2 / M阻滞

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Aurora-A, a serine-threonine kinase, is frequently overexpressed in various human cancers including hepatocellular carcinoma. Aurora-A is highly expressed in fetal liver but barely detectable in the about liver of wild-type mice; however, Aurora-A expression is transiently induced during liver regeneration. To study the phenotypic effects of Aurora-A overexpression on liver regeneration and tumorigenesis, we generated transgenic mice overexpressing human Aurora-A in the liver. Our data revealed that overexpression of Aurora-A post-hepatectomy caused an earlier entry into S phase, sustained DNA synthesis and pre-mitotic arrest in the regenerating liver. Cytokinesis failure as indicated by a significant increase in bi-nuclear hepatocytes was detected in the transgenic mice. In addition, multipolar segregation and tri-nucleation of hepatocytes were observed post-hepatectomy, which suggests that defects accumulated after first round of the hepatocyte cell cycle. Interestingly, the p53-dependent checkpoint was activated by these abnormalities indicating that p53 plays a crucial role during liver regeneration Indeed, the pre-mitotic arrest and abnormal cell death caused by Aurora-A overexpression were genetically rescued by a p53 knockout. However, tri-nucleation of hepatocytes remained in the regenerating livers of the transgenic mice with a p53 knockout background indicating that the abnormal mitotic segregation and cytokinesis failure were p53-independent. Moreover, overexpression of Aurora-A in transgenic liver led to a low incidence (3.8%) of hepatic tumor formation after a long latency period. This transgenic mouse model provides a useful system that allows the study of the physiological effects of Aurora-A on hepatocyte cell cycle progression and the genetic pathways of Aurora-A-mediated tumorigenesis in liver.
机译：Aurora-A，一种丝氨酸-苏氨酸激酶，在包括肝细胞癌在内的各种人类癌症中经常过表达。 Aurora-A在胎儿肝脏中高表达，但在野生型小鼠的大约肝脏中几乎检测不到。但是，在肝脏再生过程中会短暂诱导Aurora-A表达。为了研究Aurora-A过表达对肝脏再生和肿瘤发生的表型效应，我们生成了在肝脏中过表达人Aurora-A的转基因小鼠。我们的数据显示，肝切除术后Aurora-A的过表达导致再生肝更早进入S期，持续的DNA合成和有丝分裂前停滞。在转基因小鼠中检测到胞质分裂失败，如双核肝细胞显着增加所表明的。此外，在肝切除术后观察到肝细胞多极分离和三核化，这表明缺陷在第一轮肝细胞周期之后积累。有趣的是，这些异常激活了p53依赖的检查点，表明p53在肝再生过程中起着至关重要的作用。的确，通过p53基因敲除可以挽救因Aurora-A过表达引起的有丝分裂前停滞和异常细胞死亡。但是，肝细胞的三核保留在具有p53基因敲除背景的转基因小鼠的再生肝脏中，这表明异常的有丝分裂分离和胞质分裂失败是p53依赖性的。此外，在长时间的潜伏期后，转基因肝脏中Aurora-A的过表达导致肝肿瘤形成的发生率低（3.8％）。该转基因小鼠模型提供了一个有用的系统，可用于研究Aurora-A对肝细胞周期进程的生理影响以及肝脏中Aurora-A介导的肿瘤发生的遗传途径。

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