The gene expression of hepatic proteins responsible for DNA repair and cell proliferation in tamoxifen-induced hepatocarcinogenesis.
Altered gene expression of the DNA repair- and cell proliferation-associated proteins/enzymes was examined during the process of tamoxifen-induced hepatocarcinogenesis in female Sprague-Dawley rats. When rats were treated by gavage with a single dose of tamoxifen (20 mg/kg body weight) or with the same dose given at 24-h intervals for 2, 12 or 52 weeks, no histopathological change was observed in the liver after 2 weeks. Pathologically altered cell foci and placental form of glutathione-S-transferase (GST-P)-positive foci were observed in the liver after 12 weeks of treatment. Treatment for 52 weeks resulted in the formation of liver hyperplastic nodules that strongly expressed GST-P. During the process of carcinogenesis, changes in hepatic gene expression of DNA repair proteins/enzymes (XPA and XPC, xeroderma pigmentosum complementation groups A and C, respectively; APE, apurinic/apyrimidinic endonuclease) and of cell proliferation-associated proteins (c-myc; PCNA, proliferating cell nuclear antigen; cyclin D1, cyclin B, and p34cdc2) were examined by RT-PCR. The gene expression of XPA and APE was increased by the tamoxifen treatment for 2 or 12 weeks, but no increase was observed after the 52-week treatment. In addition, no significant change in XPC gene expression occurred at any period examined. The gene expression of c-myc, PCNA, and cyclin D1 was increased in a time-dependent fashion up to 12 weeks of treatment, and this increase was maintained up to 52 weeks of treatment. The gene expression of cyclin B and p34cdc2 was increased after the 1-day treatment, reverted to the control level at 2 and 12 weeks of treatment, and was remarkably increased after the 52-week treatment. In the present study, we demonstrate the altered gene expression of various proteins/enzymes involved in DNA repair, cell growth and the cell cycle during the process of tamoxifen-induced hepatocarcinogenesis. We discuss the relationship between the altered gene expression and hepatocarcinogenesis.
Kasahara
Toshihiko
T
Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
Kuwayama
Chitose
C
Hashiba
Masamichi
M
Harada
Tsuyoshi
T
Kakinuma
Chihaya
C
Miyauchi
Makoto
M
Degawa
Masakuni
M
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D002455:Cell Division; D019926:Cyclin B / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016259:Genes, myc; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000493:pharmacokinetics / Q000633:toxicity*; D013997:Time Factors
D002273:Carcinogens; D019926:Cyclin B; D017931:DNA Primers; D011506:Proteins; D013629:Tamoxifen; D019938:Cyclin D1