BioProject

In rodent liver, a single injection of N-nitrosodiethylamine (DEN) followed by chronic treatment with the antiepileptic drug phenobarbital (PB) promotes the outgrowth of hepatocellular tumors with activating mutations in Ctnnb1, encoding the transcription factor β-catenin. More...

In rodent liver, a single injection of N-nitrosodiethylamine (DEN) followed by chronic treatment with the antiepileptic drug phenobarbital (PB) promotes the outgrowth of hepatocellular tumors with activating mutations in Ctnnb1, encoding the transcription factor β-catenin. We now studied long-term effects of PB treatment in livers of transgenic mice with hepatocyte-specific knockout (KO) of Apc, a negative regulator of β-catenin signaling. The number of Apc KO hepatocytes present in the liver decreased with age, indicative of a selective disadvantage of Apc KO cells in the absence of PB. Following liver tumor promotion by PB in Apc KO mice for 9 months, tumor burden was quantified and histological appearance, gene expression profiles, and activity of oncogenic signaling pathways of the tumors were analyzed. In Apc KO mice fed with PB, we observed an increased hepatic tumor volume fraction and tumor multiplicity, as compared to non-promoted animals. Tumors in the PB-treated Apc KO group were mostly eosinophilic hepatocellular adenoma with activated β-catenin, due to the deletion of Apc. These tumors exhibited striking phenotypic similarities to DEN-induced Ctnnb1-mutated tumors, regarding histological appearance and expression of marker proteins and mRNAs. A particular sub-population of tumors, Apc KO-driven basophilic hepatocellular carcinomas, exclusively appeared in the non-PB-treated group but was absent from PB-promoted livers. In conclusion, phenobarbital promotes the outgrowth of Apc-deficient, β-catenin-activated hepatocellular adenoma while simultaneously inhibiting the formation of a certain population of Apc-driven hepatocellular carcinoma. Overall design: 6 weeks old male C57BL mice with a triggerable APC knockout received a tumor initiation dose of DEN prior to 9 months of treatment with or without 0.05% Phenobarbital. We profiled mRNA expression in liver tissue to assess the effects of the APC knockout on tumor development with PB. Less...