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 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 (approximately 6-fold) and c-myc (approximately 7-fold) mRNA levels were observed in liver tumors compared with liver from control rats. A slight but non-significant increase in mRNA for both of these genes was observed in tumors compared with surrounding non-lesion liver tissue (approximately 2-fold). Increases in mRNA expression of c-met (approximately 3-fold) and c-myc (approximately 5-fold) were also detected in non-lesion liver from WY-14,463-exposed animals compared 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 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 naive rats. PP-activated receptor-alpha mRNA levels were significantly increased (approximately 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 and PP-activated receptor-alpha are not major determinants of PP-induced hepatocarcinogenesis.
Miller
R T
RT
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.
Glover
S E
SE
Stewart
W S
WS
Corton
J C
JC
Popp
J A
JA
Cattley
R C
RC
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008830:Microbodies / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D011743:Pyrimidines / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D012307:Risk Factors; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D002273:Carcinogens; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C006253:pirinixic acid; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases