Hepatocarcinogens induce decrease in mRNA transcripts of receptors for insulin and epidermal growth factor in the rat liver.

Abstract

Gene expression of the receptors for insulin and epidermal growth factor (EGF) was studied in the livers of rats after a single injection of a hepatocarcinogen diethylnitrosamine (DEN) 100 mg/kg or after feeding the animals N-acetylaminofluorene (AAF) 0.02% w/w. DEN induced a time-dependent decrease in mRNA transcription of the receptors for insulin (10.3 and 8.5 Kb) and EGF (10.0, 5.8 and 2.8 Kb), evident already after 4 hours, reaching a nadir of 10-20% of the initial level between 16 and 24 hours and returning to normal by 10 days. In rats fed AAF, transcription of both receptor genes decreased to less than 20% of the control values after 2 days. In the livers of rats treated with DEN, that developed hepatocellular carcinomas one year later, expression of both receptors was also very low. DNA showed no changes. The results suggest that the hepatocarcinogens or their metabolites decrease RNA transcription or destabilize the steady state RNA level of both receptors in the early phase of toxic effect and that some tumor-derived products may be involved in the same phenomenon in the later stage of tumor development.