Journal Article

Effect on the expression of c-<i>met</i>, c-<i>myc</i> and PPAR-α in liver and liver tumors from rats chronically exposed to the hepatocarcinogenic peroxisome proliferator WY-14, 643

R.T. Miller, S.E. Glover, W.S. Stewart, J.C. Corton, J.A. Popp and R.C. Cattley

in Carcinogenesis

Volume 17, issue 6, pages 1337-1341
Published in print June 1996 | ISSN: 0143-3334
Published online June 1996 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/17.6.1337
Effect on the expression of c-met,
                        c-myc and PPAR-α in liver and liver tumors from rats
                    chronically exposed to the hepatocarcinogenic peroxisome proliferator WY-14,
                    643

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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-αmRNA 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-α are not major determinants of PP-induced hepatocarcinogenesis.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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