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Hepatocarcinogens induce decrease in mRNA transcripts of receptors for insulin and epidermal growth factor in the rat
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.
Insights
Hepatocarcinogens like diethylnitrosamine (DEN) and N-acetylaminofluorene (AAF) significantly decrease gene expression for insulin and epidermal growth factor (EGF) receptors in rat livers. This reduction occurs early and persists, even in tumors, suggesting a key role in liver cancer development.
Area of Science:
- Hepatology
- Molecular Biology
- Toxicology
Background:
- Insulin and epidermal growth factor (EGF) receptors play crucial roles in liver function and cell growth.
- Hepatocarcinogens are known to disrupt normal liver processes, potentially affecting receptor expression.
Purpose of the Study:
- To investigate the impact of hepatocarcinogens diethylnitrosamine (DEN) and N-acetylaminofluorene (AAF) on the gene expression of insulin and EGF receptors in rat livers.
- To understand the early and late effects of these carcinogens on receptor mRNA levels.
Main Methods:
- Rats were administered DEN or fed AAF, known hepatocarcinogens.
- Liver samples were analyzed for the mRNA transcription levels of insulin and EGF receptors at various time points.
- Hepatocellular carcinomas were monitored in DEN-treated rats one year post-injection.
Main Results:
- Both DEN and AAF induced a rapid and significant decrease in mRNA transcription for both insulin and EGF receptors.
- DEN caused a time-dependent decrease, reaching a nadir within 16-24 hours, with levels returning to normal by 10 days.
- In rats that developed hepatocellular carcinomas, expression of both receptors remained very low, while DNA showed no changes.
Conclusions:
- Hepatocarcinogens or their metabolites likely decrease RNA transcription or destabilize RNA levels of insulin and EGF receptors during the early toxic phase.
- Tumor-derived products may contribute to the sustained low expression of these receptors in later stages of liver tumor development.