Correlation of c-myc overexpression and amplification with progression of preneoplastic liver lesions to malignancy in the poorly susceptible wistar rat strain

Miglio, Maria Rosaria De; Simile, Maria M.; Muroni, Maria Rosaria; Pusceddu, Stefano; Calvisi, Diego F.; Carru, Angelo; Seddaiu, Maria A.; Daino, Lucia; Deiana, Luca; Pascale, Rosa M.; Feo, Francesco

doi:10.1002/(sici)1098-2744(199905)25:1<21::aid-mc3>3.0.co;2-s

Cited by 34 publications

(21 citation statements)

References 32 publications

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“…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.…”

Section: Epistatic Locimentioning

confidence: 99%

“…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.…”

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confidence: 99%

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Phenotypic reversion of rat neoplastic liver nodules is under genetic control

Miglio

Simile

Muroni

et al. 2003

Intl Journal of Cancer

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Low DNA synthesis and high redifferentiation (remodeling) characterize neoplastic nodules induced by chemical carcinogens in hybrid BFF1 rats, generated by crossing the susceptible F344 and resistant BN strains. We performed whole-genome scanning of BFF2 rats to identify loci controlling remodeling of nodules induced, 32 weeks after initiation with diethylnitrosamine, by the RH protocol. Remodeling nodules were identified as areas lacking uniformity of GST-P immunostaining and with irregular margins. Two loci in suggestive linkage with the percentage of remodeling nodules were identified on chromosomes 7 and 1 (LOD scores 3.85 and 2.9 at D7Rat25 and D1Mgh14). Significant dosage-negative effect of the B allele on remodeling and additive interaction between these loci were found. Individual risk of liver cancer reflects the amount of exposure to environmental agents, such as hepatitis B and hepatitis C viruses, aflatoxin B1, ethanol consumption, etc., combined with one's genetic predisposition. [1][2][3][4] Owing to the difficulty of studying the genetic mechanisms of human liver cancer, interspecies comparison has been proposed to identify susceptibility and resistance alleles responsible for polygenic control of the predisposition to human HCC. Previous studies on a murine model of hepatocarcinogenesis have led to the identification of 7 hepatocarcinogenesis susceptibility loci (Hcs1-7) and 2 resistance loci (Hcr1 and Hcr2) in crosses between susceptible and resistant strains. 5-8 Moreover, 2 susceptibility loci (hepatocarcinogenesis in female, Hcf1 and Hcf2) abrogate the inhibitory effect of ovarian hormones on liver tumorigenesis in mice. 9 Study of the genetic control of rat HCC in the hybrid strain BFF1, generated in our laboratory by crossing the BN, resistant, to the F344, susceptible, strains, 10 has shown dominant inheritance of resistance to hepatocarcinogenesis. Linkage analysis of BFF1 ϫ F344 backcross and BFF2 intercross rats 11,12 revealed the presence of 4 Hcs loci (rat Hcs1-4) and 7 Hcr loci (rat Hcr1-7). Hcs3 and Hcr2 have also been identified, and named Dhr1 and Drh2, in intercrosses between the (F344 ϫ DRH)F1 rats. 13 A putative suppressor gene (rccϩ), mapping to chromosome 12p, critical for determining the sensitivity of rats to diethylnitrosamine-induced liver carcinogenesis, has been identified in MHC-recombinant rat ACP strains, congenic for the MHC-linked growth reproduction complex (grc) region. 14 Clonal expansion of initiated cells in rat liver carcinogenesis is characterized by the progressive development of foci of preneoplastic hepatocytes and neoplastic nodules exhibiting fast growth and a number of morphologic, biochemical and molecular commonalties with preneoplastic and neoplastic human liver lesions. 4,15,16 Most early preneoplastic and neoplastic liver lesions undergo progressive decreases in biochemical marker expression and growth rate and finally regress (remodeling, phenotypic reversion [17][18][19][20][21][22] ). Relatively few persistent lesions are thought to be precurso...

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Section: Epistatic Locimentioning

confidence: 99%

mentioning

confidence: 99%

Phenotypic reversion of rat neoplastic liver nodules is under genetic control

Miglio

Simile

Muroni

et al. 2003

Intl Journal of Cancer

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“…Reverse transcription-polymerase chain reaction (RT-PCR) was performed by a modification of the comparative PCR method. 38,39 In brief, master solutions, containing 0.8 µg/µL of total RNA from different tissues, were diluted 1:2, 1:4, and 1:8 (vulval). The reaction mixture was made up by adding 43 µL of water to Eppendorf tubes containing predispersed Ready-to-Go beads (Amersham Pharmacia Biotech, Piscataway, NJ); 5-µL aliquots of each mRNA dilution were added to a series of 3 tubes per each tissue, followed up by the appropriate primers (1 µL each; Table 1).…”

Section: Animals and Treatmentmentioning

confidence: 99%

Implication of Bcl-2 family genes in basal and d-amphetamine-induced apoptosis in preneoplastic and neoplastic rat liver lesions

et al. 2000

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Molecular mechanisms of basal and D-amphetamine (AMPH)-induced apoptosis were studied in rat liver nodules, 12 (N12) and 30 (N30) weeks after initiation, and in hepatocellular carcinoma (HCC) induced by diethylnitrosamine in rats subjected to resistant hepatocyte model. Basal apoptosis in hematoxylin/eosin-and propidium iodidestained sections was higher in nodules and HCC than in normal livers. It sharply increased in all tissues 4 hours after AMPH treatment (10 mg/kg), and declined to basal levels at 8 to 12 hours in liver and N12, but remained high up to 18 hours in N30 and HCC. c-myc, Tgf-␣, p53, and Bcl-X S messenger RNA (mRNA) levels were higher, and Bcl-2 mRNA was lower in N12 and/or N30 and HCC than in normal liver. Four hours after AMPH injection, increase in c-myc and decreases in Bcl-2 and Bcl-X L mRNAs occurred in all tissues, whereas p53, Bax, and Bcl-X S mRNAs increased in N30 and HCC. These changes disappeared in liver and N12 at 18 hours, but persisted in N30 and HCC. c-Myc, P53, Bcl-2, and Bax proteins in normal liver and HCC ؎ AMPH showed similar patterns. Tgf-␤1, Tgf-␤-RIII, CD95, and CD95L mRNA levels underwent slight or no changes in any tissue ؎ AMPH. Basal Hsp27 expression was high in nodules and HCC, and was stimulated by AMPH in liver and N12, but not in N30 and HCC. These data suggest a role of dysregulation of Bcl-2 family genes and, at least in atypical lesions, of p53 overexpression, in basal and AMPHinduced apoptosis in nodules and HCCs. Hsp27 does not appear to sufficiently protect atypical lesions against apoptosis. (HEPATOLOGY 2000;31:956-965.)It is estimated that during rat liver carcinogenesis induced by chemicals, a number of initiated hepatocytes undergo apoptotic cell death. 1 Tumor promoters stimulate proliferation and inhibit apoptosis of initiated cells, thus inducing the development of preneoplastic foci of altered hepatocytes. Several studies have shown that the cessation of the administration of tumor promoters is followed up by enhanced apoptosis of hepatocytes in these lesions. [2][3][4][5][6] The molecular mechanisms underlying this phenomenon during the regression of liver hyperplasia induced by promoters have not yet been completely clarified, although a role of TGF-␤1 has been postulated. 5,6 Moreover, recent evidence indicates that the inhibition of apoptosis by nongenotoxic hepatocarcinogens is associated with overexpression of Bcl-2 and Bcl-X L . 7 The growth of initiated hepatocytes leads to the development of persistent liver nodules and hepatocellular carcinomas (HCCs). These lesions exhibit a high rate of cell proliferation and cell death by apoptosis, with a slight prevalence of cell production on cell loss, which allows their slow progression to more malignant stages. 1,4,8 Persistent nodules and HCCs are highly susceptible to some apoptosisinducing treatments, which can inhibit their evolution to more malignant stages. 4,9,10 The mechanisms underlying high constitutive apoptosis of chemically induced preneoplastic and neoplastic liver lesions, in vivo, a...

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“…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] . Taken together, these observations suggest the existence of some connections between c-Myc and the susceptibility genes that regulate redifferentiation.…”

Section: Cell Cycle Deregulationmentioning

confidence: 97%

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

Feo¹,

Frau²,

Pascale³

2008

WJG

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Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma (HCC). Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway (BN) rats. Unrestrained extracellular signal-regulated kinase (ERK) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (DUSP1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-kB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-α transgenic mice. iNOS, IKK/NF-kB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.

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Correlation of c-myc overexpression and amplification with progression of preneoplastic liver lesions to malignancy in the poorly susceptible wistar rat strain

Cited by 34 publications

References 32 publications

Phenotypic reversion of rat neoplastic liver nodules is under genetic control

Phenotypic reversion of rat neoplastic liver nodules is under genetic control

Implication of Bcl-2 family genes in basal and d-amphetamine-induced apoptosis in preneoplastic and neoplastic rat liver lesions

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

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