Induction of GST-P-positive proliferative lesions facilitating lipid peroxidation with possible involvement of transferrin receptor up-regulation and ceruloplasmin down-regulation from the early stage of liver tumor promotion in rats.
To elucidate the role of metal-related molecules in hepatocarcinogenesis, we examined immunolocalization of transferrin receptor (Tfrc), ceruloplasmin (Cp) and metallothionein (MT)-1/2 in relation to liver cell foci positive for glutathione-S-transferase placental form (GST-P) in the early stage of tumor promotion by fenbendazole (FB), phenobarbital, piperonyl butoxide or thioacetamide in a rat two-stage hepatocarcinogenesis model. To estimate the involvement of oxidative stress responses to the promotion, immunolocalization of 4-hydroxy-2-nonenal, malondialdehyde and acrolein was similarly examined. Our findings showed that MT-1/2 immunoreactivity was not associated with the cellular distribution of GST-P and proliferating cell nuclear antigen, suggesting no role of MT-1/2 in hepatocarcinogenesis. We also found enhanced expression of Tfrc after treatment with strong tumor-promoting chemicals. With regard to Cp, the population showing down-regulation was increased in the GST-P-positive foci in relation to tumor promotion. Up-regulation of Tfrc and down-regulation of Cp was maintained in GST-P-positive neoplastic lesions induced after long-term promotion with FB, suggesting the expression changes occurring downstream of the signaling pathway involved in the formation of GST-P-positive lesions. Furthermore, enhanced accumulation of lipid peroxidation end products was observed in the GST-P-positive foci by promotion. Post-initiation treatment with peroxisome proliferator-activated receptor alpha agonists did not enhance any such distribution changes in GST-P-negative foci. The results thus suggest that facilitation of lipid peroxidation is involved in the induction of GST-P-positive lesions by tumor promotion from an early stage, and up-regulation of Tfrc and down-regulation of Cp may be a signature of enhanced oxidative cellular stress in these lesions.
Mizukami
Sayaka
S
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
Ichimura
Ryohei
R
Kemmochi
Sayaka
S
Taniai
Eriko
E
Shimamoto
Keisuke
K
Ohishi
Takumi
T
Takahashi
Miwa
M
Mitsumori
Kunitoshi
K
Shibutani
Makoto
M
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens; D002570:Ceruloplasmin / Q000378:metabolism*; D003300:Copper / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D051549:Glutathione S-Transferase pi / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D018384:Oxidative Stress; D047493:PPAR alpha / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011990:Receptors, Transferrin / Q000378:metabolism*; D015854:Up-Regulation
D002273:Carcinogens; D047493:PPAR alpha; D011990:Receptors, Transferrin; D003300:Copper; D008668:Metallothionein; D007501:Iron; D002570:Ceruloplasmin; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat