Disruption of redox homeostasis in the transforming growth factor-α c-myc transgenic mouse model of accelerated hepatocarcinogenesis
Disruption of redox homeostasis in the transforming growth factor-α c-myc transgenic mouse model of accelerated hepatocarcinogenesis
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DOI：
10.1074/jbc.273.25.15846
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发表时间：
1998-06-19
影响因子：
4.8
通讯作者：
Thorgeirsson, SS
中科院分区：
文献类型：
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作者：
Factor, VM;Kiss, A;Thorgeirsson, SS
在以前的研究中，我们已经证明，转化生长因子（TGF）-α/c-myc双转基因小鼠表现出增强的细胞增殖率，积累广泛的DNA损伤，并在4至8个月龄之间发展成多个肝脏肿瘤。为了阐明可能导致在该转基因模型中观察到的遗传毒性和致癌作用的生化事件，在肝肿瘤发生之前检查了肝脏中氧化还原稳态的几个参数。到2月龄时，通过过氧化物敏感性荧光染料2 '，7'-二氯荧光素二乙酸酯测定活性氧的产生，与野生型或c-myc单转基因细胞相比，在TGF-α/c-myc转基因肝细胞中显著升高，并且与脂质过氧化的增加平行发生。伴随着氧化剂水平的上升，抗氧化剂的防御能力下降，包括总谷胱甘肽含量和谷胱甘肽过氧化物酶的活性，而硫氧还蛋白还原酶的活性没有改变。然而，在TGF-α/c-myc小鼠中发生的肝肿瘤显示硫氧还蛋白还原酶活性增加和谷胱甘肽过氧化物酶活性非常低。此外，在转基因小鼠中，早在5周龄时就在mtDNA中检测到特异性缺失。这些数据提供了实验证据，表明小鼠肝脏中TGF-α和c-myc转基因的共表达促进了活性氧的过度产生，从而产生了氧化应激环境。这一现象可能解释了在TGF-α/c-myc小鼠模型中观察到的大量DNA损伤和肝癌发生的加速。
In previous studies we have demonstrated that transforming growth factor (TGF)-alpha/c-myc double transgenic mice exhibit an enhanced rate of cell proliferation, accumulate extensive DNA damage, and develop multiple liver tumors between 4 and 8 months of age. To clarify the biochemical events that mag be responsible for the genotoxic and carcinogenic effects observed in this transgenic model, several parameters of redox homeostasis in the liver were examined prior to development of hepatic tumors, By 2 months of age, production of reactive oxygen species, determined by the peroxidation-sensitive fluorescent dye, 2',7'-dichlorofluorescin diacetate, was significantly elevated in TGF-alpha/c-myc transgenic hepatocytes versus either wild type or c-myc single transgenic cells, and occurred in parallel with an increase in Lipid peroxidation. Concomitantly with a rise in oxidant levels, antioxidant defenses were decreased, including total glutathione content and the activity of glutathione peroxidase, whereas thioredoxin reductase activity was not changed. However; hepatic tumors which developed in TGF-alpha/c-myc mice exhibited an increase in thioredoxin reductase activity and a very low activity of glutathiolae peroxidase. Furthermore, specific deletions were detected in mtDNA as early as 5 weeks of age in the transgenic mice. These data provide experimental evidence that co-expression of TGF-alpha and c-myc transgenes in mouse liver promotes overproduction of reactive oxygen species and thus creates an oxidative stress environment. This phenomenon may account for the massive DNA damage and acceleration of hepatocarcinogenesis observed in the TGF-alpha/c-myc mouse model.