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Sequential changes in hepatocarcinogenesis induced by diethylnitrosamine plus thioacetamide in Fischer 344 rats: induction of gankyrin expression in liver fibrosis, pRB degradation in cirrhosis, and methylation of p16(INK4A) exon 1 in hepatocellular carcinoma.

Authors
Park, TJ; Kim, HS; Byun, KH; Jang, JJ; Lee, YS; Lim, IK
Citation
Molecular carcinogenesis, 30(3):138-150, 2001
Journal Title
Molecular carcinogenesis
ISSN
0899-19871098-2744
Abstract
To clarify the sequential changes in pRB and p16 during different stages of hepatocarcinogenesis such as fibrosis, cirrhosis, hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC), male Fischer 344 rats were singly injected with diethylnitrosamine (DEN), immediately followed with phenobarbital for 1 wk and then thioacetamide (TAA) for 39 wk in drinking water. Rats were killed at 9, 20, 30, and 40 wk after DEN initiation and changes of pRB level, p16 gene hypermethylation, and in vivo gankyrin expression were examined. Histologic examination showed stepwise appearances of fibrosis, cirrhosis, HCA, and HCC at weeks 9, 20, 30, and 40, respectively. Hypermethylation of p16 exon 1 was not found until HCA but appeared in 50% of the rats with HCC accompanied by complete loss of its mRNA expression. The amount of glutathione S-transferase--gankyrin bound to pRB and pRB degradation in the liver depended on the concentration of gankyrin and incubation time. Gankyrin expression preceded pRB degradation in liver cirrhosis. In conclusion, gankyrin expression induced in liver fibrosis accelerated the degradation of pRB during liver cirrhosis, and inactivation of p16 exon 1 by DNA hypermethylation occurred during the progression of tumor cells to poorly differentiated HCC. Inactivation of pRB and/or p16 resulted in complete loss of regulation in the cell-division cycle during early and late stages, respectively, of hepatocarcinogenesis. Mol. Carcinog. 30:138--150, 2001.
MeSH terms
AnimalsBase SequenceCocarcinogenesisCyclin-Dependent Kinase Inhibitor p16/geneticsCyclin-Dependent Kinases/metabolismCyclins/metabolismDNA MethylationDiethylnitrosamineExonsGenes, RetinoblastomaLiver Cirrhosis/metabolism*Liver Neoplasms, Experimental/chemically induced*Liver Neoplasms, Experimental/geneticsLiver Neoplasms, Experimental/pathologyMaleMolecular Sequence DataOncogene Proteins/biosynthesis*Polymerase Chain ReactionProteasome Endopeptidase ComplexProto-Oncogene ProteinsRatsRats, Inbred F344Thioacetamide
DOI
10.1002/mc.1022
PMID
11301474
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Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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