Study of effects of oxidative stress on tumorigensis in LEC rats that shows a high incidence of spontaneous liver cancer.

我们研究了氧化应激对自发性肝癌高发LEC大鼠肿瘤发生的影响。虽然铜和铁在LEC大鼠肝脏中以年龄依赖的方式积累，但我们发现，铜在LEC大鼠肝脏中的积累诱导DNA链断裂，而铁的积累则不会。大鼠LEC细胞存在潜在致死损伤的缓慢修复，而不存在潜在致死损伤的快速修复。dna依赖性蛋白激酶（DNA-PK）抑制剂Wortmannin增强对照大鼠细胞的放射敏感性，但对LEC大鼠细胞没有增强作用。虽然氧化应激在DNA中产生多种损伤，但双链断裂（DSBs）似乎是大多数氧化应激诱导的细胞死亡的原因。dsb的修复在快速修复PLD的固定中起着重要的作用。DNA-PK是一种异三聚体复合物，由两个组分组成：一个大的催化亚基（DNA-PKcs）和dna靶向组分（Ku 70和Ku 80）。在对照细胞中，Ku蛋白在DSBs产生后在细胞核中积累，而在LEC细胞中则没有。LEC大鼠细胞经S期氧化应激处理后，出现G2/ m期细胞异常积聚。LEC大鼠细胞经各种应激处理后，对诱导凋亡也表现出较高的敏感性。这些结果表明，氧化应激后dsb修复缺陷和一些信号转导通路异常可能与LEC大鼠肝癌的高发有关。

We investigated effects of oxidative stress on tumorigensis in LEC rats that shows a high incidence of spontaneous liver cancer.1. Although copper and iron accumulated in the liver of LEC rats in an age-dependent manner, we showed that copper accumulation in the liver of LEC rats induced DNA strand breaks, but accumulation of iron did not.2. The slow repair of potentially lethal damage (PLD) occurred in LEC rat cells but not the fast repair of PLD.Wortmannin, an inhibitor of DNA-dependent protein kinase (DNA-PK) enhances the radiosensitivity of control rat cells but not that of LEC rat cells. Although oxidative stress produces a variety of lesions in DNA, double-strand breaks (DSBs) appear to be responsible for most oxidative stress-induced cell death. Repair of DSBs plays an important role in the fixation of fast-repairing PLD.DNA-PK that is a heterotrimeric complex comprised of two components : a large catalytic subunit (DNA-PKcs) and DNA-targeting component (Ku 70 and Ku 80). In the control cells Ku proteins accumulated in the nucleus after production of DSBs, but did not in LEC rat cells.3. LEC rat cells showed an abnormal accumulation of G2/M-phase cells after treatment with oxidative stress at S phase. LEC rat cells also showed a higher sensitivity to induction of apoptosis after treatment of the cells with a variety of stress.These results suggest that a deficiency of DSBs repair and an abnormality of some signal transduction pathways following oxidative stress may be associated with a high incidence of liver cancer of LEC rats.