Differential intracellular signalling induced by TGF-β in rat adult hepatocytes and hepatoma cells: Implications in liver carcinogenesis

The transforming growth factor-beta (TGF-β) regulates hepatocyte growth, inhibiting proliferation and inducing apoptosis. Indeed, escaping from the TGF-β suppressor actions might be a prerequisite for liver tumour progression. In this work we show that TGF-β plays a dual role in regulating apoptosis in FaO rat hepatoma cells, since, in addition to its pro-apoptotic effect, TGF-β also activates survival signals, such as AKT, the epidermal growth factor receptor (EGFR) being required for its activation. TGF-β induces the expression of the EGFR ligands transforming growth factor-alpha (TGF-α) and heparin-binding EGF-like growth factor (HB-EGF) and induces intracellular re-localization of the EGFR. Cells that overcome the apoptotic effects of TGF-β undergo morphological changes reminiscent of an epithelial-mesenchymal transition (EMT) process. In contrast, TGF-β does not activate AKT in adult hepatocytes, which correlates with lack of EGFR transactivation and no response to EGFR inhibitors. Although TGF-β induces TGF-α and HB-EGF in adult hepatocytes, these cells show very low expression of TACE/ADAM 17 (TNF-α converting enzyme), which is required for EGFR ligand proteolysis and activation. Furthermore, adult hepatocytes do not undergo EMT processes in response to TGF-β, which might be due, at least in part, to the fact that F-actin re-organization induced by TGF-β in FaO cells require the EGFR pathway. Finally, results indicate that EGFR transactivation does not block TGF-β-induced cell cycle arrest in FaO cells, but must be interfering with the pro-apoptotic signalling. In conclusion, TGF-β is a suppressor factor for adult quiescent hepatocytes, but not for hepatoma cells, where it plays a dual role, both suppressing and promoting carcinogenesis.