Vitamin E Reduces Chromosomal Damage and Inhibits Hepatic Tumor Formation in a T

我们之前已经证明，在小鼠肝脏中，由c-myc和转化生长因子- α (TGF-a)转基因的过度表达诱导的有丝分裂信号的慢性激活可诱导氧化应激状态。因此，我们提出活性氧（ROS）产生的增加可能是导致TGF-a/c-myc小鼠广泛染色体损伤和加速肝癌发生的原因。在这项研究中，我们发现维生素E （VE）是一种有效的自由基清除抗氧化剂，能够保护肝组织免受氧化应激，抑制c-myc癌基因的致瘤潜力。从断奶开始，饲粮中添加VE可以减少ROS的产生，同时显著抑制肝细胞增殖，同时增加肝脏中染色体和mtDNA的稳定性。同样，膳食VE减少了肝脏发育不良，增加了肝细胞的活力。在6个月大时，VE治疗使腺瘤的发生率降低了65%，并防止了恶性转化。这些结果表明，肝脏中c-myc和TGF-a过表达产生的ROS是该动物模型的主要致癌因子。此外，数据表明，饲料中添加VE可有效抑制肝癌的发展。接下来，我们分析了谷胱甘肽过氧化物酶（GPX1）的表达，因为有强有力的证据表明GPX1是一种主要的抗氧化酶，可以保护细胞免受致命的氧化应激。我们发现gpx1的催化活性和蛋白水平在TGF-a/c-myc肿瘤中显著降低（约5-7倍）。同时，我们观察到GPX1基因所在的9号染色体或其9F带的一个拷贝经常丢失。需要进一步的研究来确定GPX1作为化学预防酶在某些类型癌症中的可能作用。

We have previously shown that chronic activation of mitogenic signaling induced by overexpression of c-myc and transforming growth factor-alpha (TGF-a) transgenes in mouse liver induces a state of oxidative stress. We therefore proposed that increased reactive oxygen species (ROS) generation might be responsible for the extensive chromosomal damage and acceleration of hepatocarcinogenesis characteristic for TGF-a/c-myc mice. In this study we show that Vitamin E (VE), a potent free radical scavenging antioxidant, is able to protect liver tissue against oxidative stress and suppress tumorigenic potential of c-myc oncogene. Dietary supplementation with VE, starting from weaning, decreased ROS generation coincident with a marked inhibition of hepatocyte proliferation while increasing the chromosomal as well as mtDNA stability in the liver. Similarly, dietary VE reduced liver dysplasia and increased viability of hepatocytes. At six months of age, VE treatment decreased the incidence of adenomas by 65% and prevented malignant conversion. These results indicate that ROS generated by overexpression of c-myc and TGF-a in the liver are the primary carcinogenic agents in this animal model. Furthermore, the data demonstrate that dietary supplementation of VE can effectively inhibit liver cancer development. Next, we analyzed the expression of gluthatione peroxidase (GPX1), since there is a strong evidence that GPX1 is a major antioxidant enzyme that protects cells against lethal oxidative stress. We found that both catalytic activity and protein levels of GPX1were significantly (about 5-7 fold) reduced in TGF-a/c-myc tumors. Concomitantly, we observed a frequent loss of one copy of chromosome 9 or its band 9F where a GPX1 gene is located. Further studies are required to determine the possible role of GPX1 as a chemopreventive enzyme in certain types of cancer.