EFFECT ON THE EXPRESSION OF C-MET, C-MYC AND PPAR-ALPHA IN LIVER AND LIVER-TUMORS FROM RATS CHRONICALLY EXPOSED TO THE HEPATOCARCINOGENIC PEROXISOME PROLIFERATOR WY-14,643

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-myc is altered following regenerative stimuli in rat liver, suggesting involvement of their protein products in hepato cyte replication. In addition, increases in c-myc and c-met mRNA expre ssion are observed in multiple types of human and rodent tumors, inclu ding hepatocellular carcinoma. A study was designed to test the hypoth esis that development of PP-induced hepatic neoplasms occurs as a resu lt 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 r ats, Levels of mRNA expression were compared using Northern analysis. Significant increases in c-met (similar to 6-fold) and c-myc (similar to 7-fold) mRNA levels were observed in liver tumors compared with liv er 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 (similar to 2-fold). Increases in mRNA express ion of c-met (similar to 3-fold) and c-myc (similar to 5-fold) were al so detected in non-lesion liver from WY-14,463-exposed animals compare d with non-lesion liver from naive 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 p resent in tumors. To determine the potential involvement of the PR-act ivated receptor in PP-induced hepatocarcinogenesis, tumors were also e xamined for PP-activated receptor expression relative to surrounding l iver and liver from naive rats. PP-activated receptor-a mRNA levels we re significantly increased (similar to 6-fold) in tumors compared with naive liver, but only slightly increased over surrounding non-lesion liver tissue. These results suggest that modulation of c-met, c-myc an d PP-activated receptor-alpha are not major determinants of PR-induced hepatocarcinogenesis.