Differential expression of c-jun and c-myc in N-nitroso diethylamine-induced hepatic oncogenesis in AKR mice

Expression of c-jun, c-myc, c-fos and c-Ha-ras was examined and correlated with the various stages of N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in male AKR mice. The treated groups were given NDEA 100 ppm, in drinking water for 120 days. The histopathology along with the expression of oncogenes were studied at different durations of treatment such as after 1 day, 3 days 6 days, 9 days, 15 days, 20 days 30 days, 60 days, 90 days and 120 days of treatment. The results of histological investigation indicate mild hyperplasia and aniosonucleosis at 30 days of treatment and prominent pathological features from 60 days onwards until the appearance of hepatocarcinoma at 120 days even without the development of any preneoplastic or neoplastic nodule. The results of the Northern blot hybridization clearly indicate an increased expression of c-jun from 15 days onwards. This overexpression of c-jun at such an early stage indicates its association with the events earlier than the neoplastic changes. However, the persistent overexpression of c-jun at all durations of treatment indicates its association with the events during the later stage of hepatocarcinogenesis, whereas c-myc overexpression starts from 30 days of treatment and persists until the end of the experiment, i.e. 120 days of treatment. However, the results of densitometric quantification indicate that the extent of increase expression of c-myc is less than that of c-jun expression until 1 month of treatment, after which the induction of c-myc exceeds the expression of c-jun. Thus, the overexpression of c-myc from 2 months onwards might be playing a critical role in maintenance of the malignant phenotype. On the other hand, the expressions of c-fos and c-Ha-ras do not have any alteration during NDEA treatment. Thus, our data demonstrate the involvement of c-jun and c-myc in NDEA-induced hepatocarcinogenesis in AKR mice.