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

• Published in: Hepatology (Baltimore, Md.) Vol. 35; no. 6; pp. 1341 - 1350
• Main Authors: Pascale, Rosa M., Simile, Maria M., De Miglio, Maria R., Muroni, Maria R., Calvisi, Diego F., Asara, Giuseppina, Casabona, Daniela, Frau, Maddalena, Seddaiu, Maria A., Feo, Francesco
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier Inc 01.06.2002; W.B. Saunders; Wiley
• Subjects: Animals; Biological and medical sciences; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Cycle Proteins - metabolism; Cyclin A - genetics; Cyclin D1 - genetics; Cyclin E - genetics; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Digestive system; Disease Models, Animal; DNA-Binding Proteins; E2F Transcription Factors; E2F1 Transcription Factor; G1 Phase - genetics; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Investigative techniques, diagnostic techniques (general aspects); Liver - pathology; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - pathology; Male; Medical sciences; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phosphorylation; Proto-Oncogene Proteins c-myc - genetics; Rats; Rats, Inbred BN; Rats, Inbred F344; Rats, Wistar; Retinoblastoma Protein - metabolism; S Phase - genetics; Transcription Factor DP1; Transcription Factors - genetics; Transcription Factors - metabolism; Immunopathology; Deregulation; Rat; Liver; Rodentia; Gene overexpression; Hepatic disease; Carcinogenesis; Vertebrata; G1 Phase; Mammalia; Animal; Cell cycle; Fibrosis; Predisposition; Digestive diseases; Genetics
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1053/jhep.2002.33682

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. (H EPATOLOGY 2002;35:1341-1350.)