De Miglio, Maria Rosaria and Virdis, Patrizia and Calvisi, Diego Francesco and Frau, Maddalena and Muroni, Maria Rosaria and Simile, Maria Maddalena and Daino, Lucia and Careddu, Giovanni Mario and Sanna Passino, Eraldo and Pascale, Rosa Maria and Feo, Francesco (2007) Mapping a sex-hormone sensitive gene determining female resistance to liver carcinogenesis in a congenic F344.bn-hcs4 rat. Journal of Hepatology, Vol. 46 (Supplement 1), s34. ISSN 0168-8278. Article.
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Background and Aims: Hepatocellular carcinoma (HCC) is prevalently male associated in humans and rodents, but the genes responsible for female resistance to hepatocarcinogenesis remain unknown. Hepatocarcinogenesis is controlled by various genes in susceptible F344 and resistant BN rats. Seven hepatocarcinogenesis susceptibility (Hcs) loci, determining rat susceptibility to HCC, have been identified. Among them, allelic variant of Hcs4 locus in the BN rat strain (B alleles), on centromeric RNO16, controls neoplastic liver nodule volume. To investigate whether Hcs4 locus is implicated in the determination of rat genetic traits, we constructed the F344.BN-Hcs4 recombinant congenic strain (RCS). Methods: RCS was generated by introgressing a 4.41 cM portion of Hcs4 from BN strain in an isogenic F344 background. Male and female congenics were gonadectomized, with some gonadectomized animals being treated with h-estradiol 17-acetate and testosterone. Rats were initiated by diethylnitrosamine and treated according to the “resistant hepatocyte” model. Livers were excised and processed for H&E staining and proliferating cell nuclear antigen (PCNA) immunohistochemistry. Genotyping was done using 128 polymorphic microsatellite markers. Gene expression was assessed by using reverse transcription-PCR. Results: Lesion volume and positivity for PCNA were much higher in lesions of F344 than BN rats, of both sexes. These parameters were lower in females than males. Lesion volume and PCNA values of male RCS were similar to those of F344 rats, but corresponded in females to those of BN females. Carcinomatous nodules and HCC developed, at 32 and 60 weeks, respectively, in male F344 and congenics and, rarely, in F344 females. BN and congenic females developed only eosinophiliciclear cells nodules. Gonadectomy of congenic males, followed by (i-estradiol administration, caused development of preneoplastic lesions comparable to those from BN females. Administration of testosterone to gonadectomized females led to development of preneoplastic lesions as in F344 males. Conclusions: The data indicate a role of homozygous B alleles at Hcs4 in determination of phenotypic patterns of female RCS, and presence at Hcs4 locus of a high penetrance gene(s), activated by estrogens and inhibitedunaffected by testosterone, conferring resistance to females, whose B alleles provide higher resistance.
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