Expression of the c-myc, c-fos and c-ras_Ha protooncogenes during sex-differentiated rat liver carcinogenesis in the resistant hepatocyte model

The expression of the protooncogenes c-myc, c-los and c-ras^Ha has been studied in rats treated according to the resistant hepatocyte model. Protooncogene expression was studied in male and female rat liver during the selection phase, when the outgrowth of putative preneoplastic foci/nodules is markedly faster in males, and compared with the expression in advanced nodules and hepatocellular carcinomas in males. During the first 16 h after partial hepatectomy the expression of c-los and c-myc showed transient, 2- to 3-fold, increases in both sexes, both in initiated and in 'control' animals, receiving the selection/promotion regimen but no diethyl nitrosamine, with a maximum at 0.5 and 2-4 h respectively. c-ras^Ha exhibited a moderate increase (1.5-fold) at 16-24 h in all groups. A second increase in c-myc expression (2-fold) started 24 h after partial hepatectomy and lasted over the entire selection period in initiated males, while it was unchanged in females and uninitiated males. The c-fos expression also showed a short-lived increase 24 h post partial hepatectomy in initiated males. The expression of c-myc and c-los was increased 2- to 4-fold in both preneoplastic nodules and hepatocellular carcinomas, whereas c-ras^Ha expression was unchanged. In conclusion, sex differences were observed in the expression of c-myc and c-los during the early outgrowth of preneoplastic lesions, possibly reflecting a connection between the expression of these genes and the sex differentiated response to promotion in the resistant hepatocyte model. Furthermore, an overexpression also in later stages of liver carcinogenesls might indicate that expression of the protooncogenes in question is related to the entire process of multistep carcinogenesis in this model.