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

Pascale, Rosa Maria and Simile, Maria Maddalena and De Miglio, Maria Rosaria and Muroni, Maria Rosaria and Calvisi, Diego Francesco and Asara, Giuseppina and Casabona, Daniela and Frau, Maddalena and Seddaiu, Maria Antonietta and Feo, Francesco (2002) Cell cycle deregulation in liver lesions of rats with and without genetic predisposition to hepatocarcinogenesis. Hepatology, Vol. 35 (6), p. 1341-1350. eISSN 1527-3350. Article.

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DOI: 10.1053/jhep.2002.33682

Abstract

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.

Item Type:Article
ID Code:1229
Status:Published
Refereed:Yes
Uncontrolled Keywords:Hepatic disease, digestive diseases, G1 phase, fibrosis, gene overexpression
Subjects:Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Wiley
eISSN:1527-3350
Copyright Holders:© 2002 by the American Association for the Study of Liver Diseases
Deposited On:18 Aug 2009 10:04

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