Epigenetic reprogramming of liver cells in tamoxifen-induced rat hepatocarcinogenesis.
Tamoxifen, a nonsteroidal anti-estrogen, is a potent genotoxic hepatocarcinogen in rats, with both tumor initiating and promoting properties. Recently it has been demonstrated that genotoxic carcinogens, in addition to exerting genotoxic effects, often cause epigenetic alterations and these induced epigenetic changes may play important mechanistic role in carcinogenesis. In the present study, we investigated the role of tamoxifen-induced epigenetic changes in hepatocarcinogenic process. The results of the study showed that exposure of female F344 rats to tamoxifen resulted in progressive loss of CpG methylation in regulatory sequences of long interspersed nucleotide elements (LINE-1) and prominent increase in expression of LINE-1 elements and c-myc proto-oncogene. The accumulation of tamoxifen-induced DNA lesions was accompanied by the decreased level of Rad51, Ku70, and DNA polymerase beta (Polbeta) proteins that play a crucial role in maintenance of genomic stability. Furthermore, feeding rats with tamoxifen-containing diet led to increased regenerative cell proliferation, as indicated by the increased level of Ki-67 and proliferating cell nuclear antigen (PCNA) proteins. These data indicate that exposure of animals to genotoxic hepatocarcinogen tamoxifen led to early phenotypical alterations in livers characterized by emergence of epigenetically reprogrammed cells with a specific cancer-related epigenetic phenotype prior to tumor formation.
Tryndyak
Volodymyr P
VP
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Kovalchuk
Olga
O
Muskhelishvili
Levan
L
Montgomery
Beverly
B
Rodriguez-Juarez
Rocio
R
Melnyk
Stepan
S
Ross
Sharon A
SA
Beland
Frederick A
FA
Pogribny
Igor P
IP
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D018899:CpG Islands; D019175:DNA Methylation; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D004965:Estrogen Antagonists / Q000633:toxicity*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D000072200:Ku Autoantigen; D008113:Liver Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics*; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000633:toxicity*
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D012333:RNA, Messenger; D013629:Tamoxifen; D051135:Rad51 Recombinase; C495155:Rad51 protein, rat; D019951:DNA Polymerase beta; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen