Spectrum of molecular changes during hepatocarcinogenesis induced by DEN and other chemicals in Fisher 344 male rats [Mechanisms of Ageing and Development 123 (2002) 1665-1680].
Unlike other tissues such as breast, colon and renal cell carcinoma, it is not an easy task to single out any representative oncogene or tumor suppressor genes in the development of hepatocellular carcinoma (HCC), which play a pivotal role. To investigate putatively altered main pathways in HCC, F344 male rats were treated with a single injection of N-nitrosodiethylamine (DEN), followed by either twice/week injections of nodularin for 10 weeks or thioacetamide (TAA) in drinking water for 39 weeks. p53 expression was dramatic in both hepatocytes and mesenchymal cells after a single injection of DEN, however, PCR-SSCP assay could not detect any p53 mutation during the development of hepatocellular adenoma (HCA). The data indicate that wtp53 response was mostly for removal of damaged cells during the initiation of carcinogenesis. When treated with DEN-TAA, induction of gankyrin expression during hepatic fibrosis preceded the loss of pRB protein, accompanied with significant expressions of G1phase cyclins and CDKs. Moreover, p16(INK4A) exon 1 was hypermethylated during the development of poorly differentiated HCCs. These changes would result in complete inactivation of the pRB regulatory pathway during hepatocarcinogenesis. Induction of TGF-beta1 expression with loss of its receptor expression occurred rapidly in the altered hepatocytes by DEN-nodularin treatment.


CONCLUSIONS
Therefore, escape from TGF-beta1 induced apoptosis and severe degradation of pRB protein during the early stage of carcinogenesis can perform a symphony to proliferate and to transform the altered hepatocytes to tumor cells. Inactivation of p16(INK4A) and p53 genes at the later stage of carcinogenesis would endow HCC with malignancy, which is highly resistant to any therapeutic trials.
Lim
In Kyoung
IK
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Gyunggi-do, Suwon, South Korea. iklim@ajou.ac.kr
D000375:Aging / Q000502:physiology*; D000477:Alkylating Agents; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D002453:Cell Cycle / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004249:DNA Damage; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D008103:Liver Cirrhosis / Q000473:pathology / Q000503:physiopathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D010456:Peptides, Cyclic; D051381:Rats; D011916:Rats, Inbred F344; D016160:Retinoblastoma Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D000477:Alkylating Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D010456:Peptides, Cyclic; D016160:Retinoblastoma Protein; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; C063998:nodularin; D004052:Diethylnitrosamine