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Mechanisms of Hepatoblastoma Carcinogenesis in Low Birth Weight Infants

低出生体重儿肝母细胞瘤癌变机制

基本信息

批准号：
15591892
负责人：
IKEDA Hitoshi
金额：
$ 2.05万
依托单位：
Dokkyo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591892/
关键词：
Hepatoblastoma Low birth weight infants Oxidative DNA damage 酸化ストレス胎児ラット遺伝子発現 AFP 酸素 βカテニン 8-OHdG Superoxide dismutase β-catenin

项目摘要

To verify possible roles of oxygen radicals in carcinogenesis of liver cells in premature babies, oxygen-causing oxidative DNA damage and an antioxidant enzyme activity were examined in primary cultures of rat liver cells. After oxygen exposure, 8-OHdG was significantly accumulated in a time-dependent manner particularly in the medium of liver cells derived from newborn rats. Superoxide dismutase activity was significantly lower in liver cells of newborn rats, suggesting that it was responsible for oxidative DNA damages in liver cells of newborn rats. Next, it was examined whether oxidative stresses such as hyperoxia or hypoxia caused alterations in β-catenin gene or its expression in liver cells of newborn and fetal rats. An accumulation of β-catenin protein in the nuclei was also examined. However, no genomic alterations or nuclear accumulation of β-catenin were observed in cells exposed to oxidative stresses. Third, it was examined whether oxidative stresses affected the expression of genes relating to differentiation of liver cells in fetal rats. Liver cells derived from fetal rats (day 18) were exposed to hypoxia, hyperoxia, and hypoxia and hyperoxia, and the expression of α1-AT, HNF4, AFP, albumin were examined. The expression of AFP gene was decreased as the time of culture increased, however, this was not observed in liver cells exposed to oxidative stresses. The oxidative stresses might have caused an arrest of differentiation of developing liver cells or stimulated directly the expression of AFP gene. It was suggested that oxidative stress might be responsible for hepato-carcinogenesis by affecting the differentiation of premature liver cells.

为了验证氧自由基在早产儿肝细胞癌变中的可能作用，在大鼠肝细胞原代培养中检测了氧引起的氧化DNA损伤和抗氧化酶活性。氧暴露后，8-OHdG以时间依赖性的方式显著积累，特别是在新生大鼠肝细胞培养基中。新生大鼠肝细胞超氧化物歧化酶活性明显降低，提示其与新生大鼠肝细胞DNA氧化损伤有关。接下来，研究了氧化应激如高氧或缺氧是否会引起新生和胎儿大鼠肝细胞中β-连环蛋白基因或其表达的改变。细胞核中β-连环蛋白的积累也被检测到。然而，在暴露于氧化应激的细胞中，没有观察到基因组改变或β-连环蛋白的核积累。第三，研究氧化应激是否影响胎鼠肝细胞分化相关基因的表达。取胎鼠肝细胞（第18天）进行缺氧、高氧、低氧加高氧处理，检测α - 1- at、HNF4、AFP、白蛋白的表达。AFP基因的表达随着培养时间的增加而降低，但在氧化应激的肝细胞中没有观察到这种情况。氧化应激可能导致发育中的肝细胞分化阻滞或直接刺激AFP基因的表达。提示氧化应激可能通过影响过早肝细胞的分化而参与肝癌的发生。