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

Abstract

P revious studies on genetic predisposition to hepatocellular carcinoma (HCC) of rats led to identification of 4 hepatocarcinogenesis susceptibility (Hcs1-4) loci, and 7 resistance (Hcr1-7) loci 1,2 (De Miglio et al., unpublished data). Resistance alleles, dominantly transmitted to the progeny, 3,4 apparently modify the activity of susceptibility loci. Recent evidence suggests the presence of at least 3 oncosuppressor genes at Hcr1 locus. 4 Molecular mechanisms underlying these effects are unknown. Available evidence suggests the existence of a relatively stable genome in neoplastic lesions of resistant rats, as shown by the absence of c-myc amplification in the lesions of a resistant Wistar rat strain, which instead is present in susceptible Fisher 344 (F344) rats. 5,6 Moreover, allelic imbalance occurs, at several chromosomes, in HCCs of susceptible (F344 x Wistar Furth)F1 rats, 7 but not in those of resistant BFF1 rats. 8 HCCs induced in LFF1 rats, generated by crossing the susceptible F344 and Long-Evans strains, show allelic imbalance at Hcs1, Hcr1, and Hcr6. 4 c-myc is located at Hcs1 in a segment syntenic to human chromosomal regions in which frequent allelic gain occurs. 9 These observations suggest that mechanisms controlling cell growth are differently affected in neoplastic liver lesions of susceptible and resistant rats.Overexpression of c-myc in c-myc-and c-myc/Tgf-␣-transgenic mice is associated with deregulation of the pRb-E2F pathway. 10 Interaction of c-Myc with various cell cycle components occurs in in vitro growing cells. 11,12 Enzymes controlling cell cycle include cyclin-dependent kinases (CDKs), activated by binding to the cyclins. 13 Complexes of CDK4 and CDK6 with D-type cyclins are required for the G1 phase progression. Further progression through G1 requires cyclin E, and passage through

Phenotypic reversion of rat neoplastic liver nodules is under genetic control

“…c-myc and c-myc target genes, including Cyclin E, E2F1 and Odc, 36 are upregulated in neoplastic liver lesions of rodents and humans, and this is influenced by genetic predisposition to hepatocarcinogenesis. 24,27,37 Genes involved in cell growth regulation located at the Hcrem2 locus include Adra2a and Adrb1, encoding adrenergic receptors ␣2a and ␤1, respectively, and Prkg1 and Cyp17, which are deregulated in rat and/or human HCC. 38,39 Cyp17 encodes cytochrome P-450-17␣, which mediates 17␣-hydroxylase and 17,20-lyase activities in the androgen biosynthesis pathway.…”

“…11,22,24 -26 The growth rate of neoplastic hepatocytes is under the control of Hcs and Hcr loci. 24,27 However, the genes and molecular mechanisms responsible for remodeling are unknown. Mapping of the genes regulating remodeling may contribute to our understanding of the mechanisms of neoplastic lesion regression and the genetically transmitted resistance to hepatocarcinogenesis.…”

Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis

“…The decrease in c-Myc expression, induced by prolonged administration of the methyl donor S-adenosylmethionine to rats, is associated with growth restraint and re-differentiation of liver lesions [20,57,58] . No differences in c-Myc expression occur in the liver of nor mal F344 and BN rats [56,58,59] . However, the expression of this gene is much higher in preneoplastic and neoplastic lesions of F344 rats than in the lesions of BN rats [56,58,59] .…”

“…No differences in c-Myc expression occur in the liver of nor mal F344 and BN rats [56,58,59] . However, the expression of this gene is much higher in preneoplastic and neoplastic lesions of F344 rats than in the lesions of BN rats [56,58,59] . c-Myc is frequently amplified in preneoplastic and neoplastic lesions of the susceptible strain, but not in the lesions of the resistant BN and Wistar strains [60] .…”

Role of DUSP1/MKP1 in tumorigenesis, tumor progression and therapy

“…The expression of DUSP1 was detected in two rat models: Fisher344 (F344) and Brown Norway(BN). Lower expression was detected in F344 rats which were susceptible to form chemical-induced HCC, while BN rats expressed higher DUSP1 which were resistant to form HCC [30,31]. Susceptibility to hepatocarcinogenesis was identified to be associated with a more pronounced activation of the ERK cascade in F344 and BN rats.…”