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 p16INK4A exon 1 in hepatocellular carcinoma

Tae Jun Park; Hong Seok Kim; Kyu Hee Byun; Ja June Jang; Yun Sil Lee; In Kyoung Lim

doi:10.1002/mc.1022

journal article Mar 01, 2001

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 p16INK4A exon 1 in hepatocellular carcinoma

Tae Jun Park Hong Seok Kim

Kyu Hee Byun Ja June Jang Yun Sil Lee In Kyoung Lim

Molecular Carcinogenesis Vol. 30 No. 3 pp. 138-150 · Wiley

View at Publisher Save 10.1002/mc.1022

Abstract

AbstractTo 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. © 2001 Wiley‐Liss, Inc.

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Published: Mar 01, 2001
Vol/Issue: 30(3)
Pages: 138-150
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Cite This Article

Tae Jun Park, Hong Seok Kim, Kyu Hee Byun, et al. (2001). 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 p16INK4A exon 1 in hepatocellular carcinoma. Molecular Carcinogenesis, 30(3), 138-150. https://doi.org/10.1002/mc.1022

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 p16INK4A exon 1 in hepatocellular carcinoma

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