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

我们以前已经表明，慢性激活的促有丝分裂信号诱导过表达的c-myc和转化生长因子-α（TGF-α）转基因在小鼠肝脏诱导的氧化应激状态。 因此，我们认为活性氧（ROS）的产生增加可能是TGF-α/c-myc小鼠广泛的染色体损伤和加速肝癌发生特征的原因。 在这项研究中，我们表明，维生素E（VE），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和抑制c-myc癌基因的致瘤潜力。 从断奶开始，饮食中补充VE，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减少肝脏发育不良和肝细胞的活力增加。 在6个月大时，VE治疗使腺瘤的发病率降低了65%，并防止了恶性转化。这些结果表明，由肝脏中c-myc和TGF-α的过表达产生的ROS是该动物模型中的主要致癌剂。 此外，数据表明，膳食补充VE可以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（GPX 1）的表达，因为有强有力的证据表明GPX 1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，在TGF-α/c-myc肿瘤中，GPX 1的催化活性和蛋白水平均显著降低（约5-7倍）。与此同时，我们观察到9号染色体或其带9 F的GPX 1基因所在的一个拷贝的频繁丢失。需要进一步的研究来确定GPX 1作为某些类型癌症的化学预防酶的可能作用。

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.