Abstract
Hepatocellular carcinoma (HCC) is prevalent in human and rodent males. Hepatocarcinogenesis is controlled by various genes in susceptible F344 and resistant Brown Norway (BN) rats. B alleles at Hcs4 locus, on RNO16, control neoplastic nodule volume. We constructed the F344.BN-Hcs4 recombinant congenic strain (RCS) by introgressing a 4.41-cM portion of Hcs4 from BN strain in an isogenic F344 background. Preneoplastic and neoplastic lesions were induced by the ‘‘resistant hepatocyte’’ protocol. Eight weeks after initiation, lesion volume and positivity for proliferating cell nuclear antigen (PCNA) were much higher in lesions of F344 than BN rats of both sexes. These variables were lower in females than in males. Lesion volume and PCNA values of male RCS were similar to those of F344 rats, but in females corresponded 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 eosinophilic/clear cells nodules. Gonadectomy of congenic males, followed by B-estradiol administration, caused a decrease in Ar expression, an increase in Er-a expression, and development of preneoplastic lesions comparable to those from BN females. Administration of testosterone to gonadectomized females led to Ar increase and development of preneoplastic lesions as in F344 males. This indicates a role of homozygous B alleles at Hcs4 in the determination of phenotypic patterns of female RCS and presence at Hcs4 locus of a high penetrance gene(s), activated by estrogens and inhibited/unaffected by testosterone, conferring resistance to females in which the B alleles provide higher resistance. (Cancer Res 2006; 66(21): 10384-90)
Highlights
Epidemiologic evidence suggests the existence in humans of a genetic predisposition to hepatocellular carcinoma (HCC) involving low-penetrance genetic variants [1]
Liver weights per 100-g body weight of Fisher 344 (F344), Brown Norway (BN), and congenic rats not treated with carcinogens ranged from 2.98 to 3.5 g in males and from 3.22 to 3.36 g in females
Genetic susceptibility to hepatocarcinogenesis of male F344, BN, and (BN Â F344)F1 rats is under control of 7 Hepatocarcinogenesis susceptibility (Hcs), 9 Hepatocarcinogenesis resistance (Hcr), and 2 Liver neoplastic nodules remodeling (Lnnr) loci, influencing the number, volume, and redifferentiation of neoplastic liver nodules, respectively [1]
Summary
Epidemiologic evidence suggests the existence in humans of a genetic predisposition to hepatocellular carcinoma (HCC) involving low-penetrance genetic variants [1]. Rodent strains with different susceptibility to HCC allowed mapping of various susceptibility and resistance loci controlling growth and differentiation of neoplastic lesions [1]. Endocrine ablation studies showed enhancement of hepatocarcinogenesis by testosterone and inhibition by ovarian hormones [4,5,6]. These effects depend on functional specific receptors [7, 8]. Because sex hormones regulate growth hormone secretion, it was hypothesized [12] that growth hormone mediates sex difference in susceptibility to HCC. Manipulation giving a feminized pattern of growth hormone secretion to rat males leads to higher basal serum levels of this hormone than in normal males [13]
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