Mechanisms of Hepatoblastoma Carcinogenesis in Low Birth Weight Infants

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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.