Vitamin E reduces chromosomal damage and inhibits hepatic tumor formation in a transgenic mouse model

Abstract

We have previously shown that chronic activation of mitogenic signaling induced by over-expression of c-myc and transforming growth factor-␣ (TGF␣) 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␣͞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 6 mo of age, VE treatment decreased the incidence of adenomas by 65% and prevented malignant conversion. These results indicate that ROS generated by over-expression of c-myc and TGF␣ 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.

Selenoprotein deficiency and high levels of selenium compounds can effectively inhibit hepatocarcinogenesis in transgenic mice

“…The trademark features of liver oncogenesis in TGFa/c-Myc mice are chronic oxidative stress resulting from increased production of reactive oxygen species and genomic instability (Factor et al, , 2000Hironaka et al, 2003;Calvisi et al, 2004). In contrast to expectations, we found that not only supplementation of the diet with high levels of Se but also Se deficiency suppressed tumorigenesis in this model.…”

“…In these mice, constitutive coexpression of c-Myc and TGFa in the liver generates an oxidative stress environment prior to tumor development and predisposes mice to a 100% incidence of HCC by 6-8 months of age (Calvisi et al, 2004). Importantly, vitamin E, a potent free radical scavenging antioxidant, was able to protect liver tissue against oxidative stress and suppress hepatic tumor formation in TGFa/c-Myc mice (Factor et al, 2000).…”

“…When used in physiological levels, Se is often viewed as antioxidant that works in concert with vitamin E. However, vitamin E decreased tumorigenesis in TGFa/ c-Myc mice (Factor et al, 2000), suggesting that at least in this mouse model, these compounds may have opposite effects. Besides, different selenoproteins may influence carcinogenesis in various ways (Gladyshev et al, 1998).…”

Telomere Shortening Correlates With Increasing Aneuploidy of Chromosome 8 in Human Hepatocellular Carcinoma *

“…In addition to telomere shortening, other mechanisms such as genomic hypomethylation and hypermethylation, oxida- tive and nitrosative DNA damage, and a defective DNA repair system appear to contribute to the development of CIN in HCC. 4,[17][18][19] The stepwise increase of CIN seems to be in line with the accumulation of genetic alterations involving proto-oncogenes and tumor suppressor genes such as p53, Rb1, EXT1, APC, nm23, DCC, BRCA1, VHL, DPC4, and WT1. 4,[20][21][22][23][24] Gains at 8q22-24 correlate with overexpression of the c-myc gene, found in most of the liver cancers.…”

Hepatocellular carcinomas in native livers from patients treated with orthotopic liver transplantation: Biologic and therapeutic implications

“…( Hepatic carcinogenesis is a multicentric process divided classically into the 3 stages of initiation, promotion, and progression. [1][2][3][4][5][6][7] Initiation, an irreversible step marked by DNA damage and mutations, confers upon initiated cells, a potential growth advantage over surrounding cells. In the proper promoting environment, initiated cells undergo clonal expansion because of less responsiveness to negative growth constraints, altered responses to signals for growth or terminal differentiation, and/or resistance to the cytotoxicity and mitoinhibitory effects of carcinogens.…”