Phenobarbital selectively promotes initiated cells with reduced TGFβ receptor levels

Phenobarbital (PB) is a potent tumor promoter in rodent liver. In this study we investigated whether PB selectively promotes a population of initiated cells with reduced levels of transforming growth factor-β (TGFβ) receptors types I, II and III. Liver tumors were induced in male Fischer F344 rats by diethylnitrosamine (DEN). Following induction the animals were divided into PB-treated (DEN/PB) and untreated groups (DEN). After 3 months of treatment half of the PB-treated rats were removed from PB for the final month (DEN/PB/OFF). At 4 months, the livers from rats in the three treatment groups were removed, tumors excised and frozen with matched surrounding normal tissue. The mRNA levels for the TGFβ receptors types I-III were significantly decreased in tumor tissue from DEN/PB rats when compared with surrounding normal liver tissue or tumors from age-matched untreated controls. In tumors from DEN/PB/OFF rats the TGFβ receptor types I-III were also significantly reduced compared with controls and not different to tumors from DEN/PB rats. There was no difference in the mRNA levels for the TGFβ receptors in tumors from rats exposed to DEN alone, when compared with the surrounding normal tissue. These results demonstrate that PB selectively promotes initiated cells with reduced levels of TGFβ types I-III receptors and suggests a mechanistic role for TGFβ in PB-induced liver tumor promotion.