Cell cycle deregulation in liver lesions of rats with and without genetic predisposition to hepatocarcinogenesis

Preneoplastic and neoplastic hepatocytes undergo c-Myc up-regulation and overgrowth in
rats genetically susceptible to hepatocarcinogenesis, but not in resistant rats. Because c-Myc
regulates the pRb-E2F pathway, we evaluated cell cycle gene expression in neoplastic nodules
and hepatocellular carcinomas (HCCs), induced by initiation/selection (IS) protocols 40
and 70 weeks after diethylnitrosamine treatment, in susceptible Fisher 344 (F344) rats, and
resistant Wistar and Brown Norway (BN) rats. No interstrain differences in gene expression
occurred in normal liver. Overexpression of c-myc, Cyclins D1, E, and A, and E2F1 genes, at
messenger RNA (mRNA) and protein levels, rise in Cyclin D1-CDK4, Cyclin E-CDK2, and
E2F1-DP1 complexes, and pRb hyperphosphorylation occurred in nodules and HCCs of
F344 rats. Expression of Cdk4, Cdk2, p16 INK4A, and p27 KIP1 did not change. In nodules
and/or HCCs of Wistar and BN rats, low or no increases in c-myc, Cyclins D1, E, and A, and
E2F1 expression, and Cyclin-CDKs complex formation were associated with p16 INK4A overexpression
and pRb hypophosphorylation. In conclusion, these results suggest deregulation
of G1 and S phases in liver lesions of susceptible rats and block of G1-S transition in lesions
of resistant strains, which explains their low progression capacity.