© 1996 Oxford University Press
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Effect on the expression of c-met, c-myc and PPAR-
in liver and liver tumors from rats chronically exposed to the hepatocarcinogenic peroxisome proliferator WY-14, 643
Chemical Industry Institute of Toxicology 6 Davis Drive, PO Box 12137, Research Triangle Park, NC 27709, USA
1To whom correspondence should be addressed
The induction of rodent hepatic tumors by peroxisome proliferators (PP) appears to depend on focal growth of hepatocytes. Expression of the oncogenes c-met and c-mycis altered following regenerative stimuli in rat liver, suggesting involvement of their protein products in hepatocyte replication. In addition, increases in c-myc and c-met mRNA expression are observed in multiple types of human and rodent tumors, including hepatocellular carcinoma. A study was designed to test the hypothesis that development of PP-induced hepatic neoplasms occurs as a result of overexpression of c-met or c-myc. Male F344 rats were exposed to WY-14, 643 for 22 or 78 weeks (1000 p.p.m. in the diet). Messenger RNA was extracted from liver tumors (78 weeks) and surrounding non-lesion liver of exposed rats and non-lesion liver from age-matched control rats. Levels of mRNA expression were compared using Northern analysis. Significant increases in c-met (
6-fold) and c-myc(7-fold) mRNA levels were observed in liver tumors compared with liver from control rats. A slight but nonsignificant increase in mRNA for both of these genes was observed in tumors compared with surrounding non-lesion liver tissue (2-fold). Increases in mRNA expression of c-met (3-fold) and c-myc (5-fold) were also detected in non-lesion liver from WY-14,463-exposed animals compared with non-lesion liver from native rats. PP exposure in rats increased c-met and c-myc expression in liver and liver tumors, but in a manner which does not correspond to the rapid proliferation of hepatocytes present in tumors. To determine the potential involvement of the PP-activated receptor in PP-induced hepatocarcinogenesis, tumors were also examined for PP-activated receptor expression relative to surrounding liver and liver from native rats. PP-activated receptor-
mRNA levels were significantly increased (6-fold) in tumors compared with native liver, but only slightly increased over surrounding non-lesion liver tissue. These results suggest that modulation of c-met, c-myc and PP-activated receptor- are not major determinants of PP-induced hepatocarcinogenesis.
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