Role of growth hormone in the regulation of the c‐myc gene during progression of sex‐differentiated rat liver carcinogenesis in the resistant hepatocyte model

In this study, we extended the previous observations of a growth hormone-regulated sex difference in hepatic c-myc expression in the resistant hepatocyte model during the selection/promotion phase, when sex differences in growth rate of enzyme-altered foci are first identified, to studies of the regulation of this gene during later stages of hepatocarcinogenesis. The expression of the c-myc gene was studied in preneoplastic nodules, hepatocellular carcinomas, and the corresponding surrounding liver of male and female Wistar rats treated according to the resistant hepatocyte model. In males, nodules isolated 8 and 11-12 mo after initiation and hepatocellular carcinomas exhibited a 2.5- to threefold higher c-myc expression than the surrounding liver. In females, no increase in c-myc expression was observed in nodules 8 mo after initiation, while nodules isolated after 11-14 mo and tumors showed a twofold and threefold increase, respectively, when compared with the surrounding tissue. Increased transcription of the c-myc gene was observed in nuclei from male nodules isolated 11 mo after initiation compared with nuclei from the surrounding liver. The difference in transcription between male nodules and surrounding tissue is similar for the first and second exon of the gene. Continuous infusion of growth hormone to nodule-bearing male rats 8 and 11 mo after initiation decreased c-myc expression in the surrounding tissue and downregulated the expression in 8-mo nodules to the level in the surrounding liver. No significant decrease in response to growth hormone treatment was seen in 11-mo nodules. In hypophysectomized nodule-bearing males, nodular c-myc remained upregulated. Taken together, the data showed that the sex difference in c-myc expression was maintained during a large part of the progression period. Furthermore, the loss of growth hormone regulation of the c-myc gene in advanced male nodules indicated an escape from normal regulatory mechanisms during progression. These findings might reflect a role for the c-myc gene in sex-differentiated rat liver carcinogenesis.