Promotive action of 2-acetylaminofluorene on hepatic precancerous lesions initiated by diethylnitrosamine in rats:Molecular study

BACKGROUND Diethylnitrosamine(DEN)induces hepatic neoplastic lesions over a prolonged period.AIM To investigate the promotive action of 2-acetylaminofluorene(2-AAF)when combined with DEN in order to develop a rat model for induction of precancerous lesion and investigate the molecular mechanism underlying the activity of 2-AAF.METHODS The pre-precancerous lesions were initiated by intraperitoneal injection of DEN for three weeks consecutively,followed by one intraperitoneal injection of 2-AAF at three different doses(100,200 and 300 mg/kg).Rats were separated into naïve,DEN,DEN+100 mg 2-AAF,DEN+200 mg 2-AAF,and DEN+300 mg 2-AAF groups.Rats were sacrificed after 10 wk and 16 wk.Liver functions,level of alpha-fetoprotein,glutathione S-transferase-P and proliferating cell nuclear antigen staining of liver tissues were performed.The mRNA level of RAB11A,BAX,p53,and Cyclin E and epigenetic regulation by long-noncoding RNA(lncRNA)RP11-513I15.6,miR-1262(microRNA),and miR-1298 were assessed in the sera and liver tissues of the rats.RESULTS 2-AAF administration significantly increased the percent area of the precancerous foci and cell proliferation along with a significant decrease in RAB11A,BAX,and p53 mRNA,and the increase in Cyclin E mRNA was associated with a marked decrease in lncRNA RP11-513I15.6 expression with a significant increase in both miR-1262 and miR-1298.CONCLUSION 2-AFF promoted hepatic precancerous lesions initiated through DEN by decreasing autophagy,apoptosis,and tumor suppression genes,along with increased cell proliferation,in a time-and dose-dependent manner.These actions were mediated under the epigenetic regulation of lncRNA RP11-513I15.6/miR-1262/miR-1298.