TRANSFORMING GROWTH-FACTOR-BETA RECEPTORS TYPE-I, TYPE-II AND TYPE-III IN PHENOBARBITAL-PROMOTED RAT-LIVER TUMORS

Rat liver tumors initiated with N-nitrosodiethylamine (DEN) followed by promotion with phenobarbital (PB) were examined for expression of transforming growth factor-beta (TGF beta) type I, II and III receptors. RNase protection and TGF beta(1) affinity labeling assays were used to determine TGF beta receptor steady-state mRNA and protein levels, respectively. We have demonstrated that all three TGF beta receptors are expressed in both normal and malignant hepatic tissues, Long-term PB administration did not alter TGF beta receptor mRNA or protein levels in normal liver, However, type I, II and III TGF beta receptor mRNA and protein levels were decreased by similar to 50% in the DEN-initiated/PB-promoted liver tumors as compared to the receptor levels in normal liver tissue surrounding the tumors, In contrast, TGF beta receptor mRNA and protein levels were unchanged in liver tumors initiated with DEN but not PR-promoted, These data demonstrate that PB promotes the formation of a tumor phenotype that is characterized by a significantly reduced number of TGF beta type I, II and III receptors, This suggests that the downregulation of TGF beta receptors in PB-promoted hepatic tumors may provide a selective growth advantage to the tumor cells by reducing the ability of TGF beta to inhibit their growth.