Study on Stress-response pathway in tumorigenesis in LEO rats that shows a high incidence of spontaneous liver cancer.

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We investigated a stress-responsive pathway in LEC rats that shows.a high incidence of spontaneous liver cancer.1. Although copper and ion accumulated in the liver of LEG rats in an age-dependent manner, copper accumulation induced DNA strand breaks in the, liver cells, but accumulation of iron did not. The amounts of DNA strand breaks produced by copper accumulation in the liver cells of female rats are not more abundant than those in the cells of male rats, although hepatic injury in female rats is more serious than in male rats.2. Treatment of LEG rats with trientine, a specific copper chelating agent, prevents the induction of DNA strand breaks, although high copper content still remain in the liver. Lignan, phenylpropanoid derivatives, prepared from flax showed protective effect on hepatic injury in rats induced by CCl_4.3. Thymocytes of LEG rats showed high sensitivities in induction of apoptosis during in vitro cultivation and X-irradiation. LEG rat fibroblasts showed high. sensitivity in induction of apoptosis by UVB irradiation. Inhibition of replication induced non-apoptotic cell death in LEG rat fibroblatst cell lines.4. We showed nuclear translocation and accumulation of Ku proteins, components of DNA-dependent protein kinase are important for repair of DNA double strand breaks (DSB) induced by X-irradiation in rat cells, and that there are some defects in maintaining the levels of Ku proteins in the nuclei of LEG rat cells.These results suggest that a deficiency of DSB repair and abnormality of some pathway responsive to a variety of stress may be associated with a high incidence of liver cancer of LEG rats.