We thank Dr. Bortolami and colleagues for their interest in our recent article showing perturbation of hepatocytic transforming growth factor β (TGF-β) signaling during progression of hepatitis C virus (HCV)-related chronic liver disorders.1 In parallel with emergence of epithelial-to-mesenchymal transition paradigm in fibrocarcinogenic steps, a large body of work has established roles for epithelial cells as important mediators of progressive fibrosis and carcinogenesis.2 Our data indicate that hepatocytes undergo transition from the tumor-suppressive TGF-β pathway, which is characteristic of mature epithelial cells, to the fibrogenic TGF-β pathway, which appears to favor the state of flux shown by the activated hepatic stellate cells (HSC), accelerating liver fibrosis while increasing risk of cancer. Our finding of hepatocytes involvement in fibrogenesis confirms the recent reports from other laboratories that mature hepatocytes can acquire a mesenchymal phenotype and undertake the activated HSC functions.3, 4
Chronic inflammation associated with persistent HCV infection is clearly the primary inducer of liver fibrosis and cancer. Fibrotic stages and necroinflammatory activities of HCV-related liver diseases therefore correlate closely with the risk of hepatocellular carcinoma (HCC). As suggested by Bortolami and colleagues, TGF-β, interleukin-1β, and DNA oxidative damage are increased in chronic hepatitis C and cirrhotic livers. These findings suggest that elevated interleukin-1β and DNA oxidative damage can alter hepatocytic TGF-β signaling in HCV-related preneoplastic lesions. TGF-β signaling of hepatocytes affected by chronic inflammation acts as a key regulatory element that offers a general framework for understanding the origins of HCV-related HCC.
Reversible shifting of Smad-dependent signaling between tumor suppression and oncogenesis in hyperactive Ras-expressing cells indicates that oncogenic activities such as cell proliferation and invasion are promoted by Smad3 phosphorylated at the linker region (pSmad3L) pathway.5 Linker phosphorylation of Smad3 indirectly inhibits C-terminal phosphorylation, minimizing Smad3 phosphorylated at the C-terminal region (pSmad3C) signaling.5 In the liver, a major function of TGF-β is to limit regenerative growth of hepatocytes in response to injury by inhibiting cell growth and inducing apoptosis. pSmad3C-mediated signaling appears to take part in cytostatic function of TGF-β such as growth inhibition and apoptosis of hepatocytes. For example, Bcl-2 repression by TGF-β requires C-terminal phosphorylation of Smad3.6 To evade apoptosis, HCC might acquire Bcl-2 overexpression induced by pSmad3L pathway. Escaping apoptosis is a critical step in the progression to full malignancy of cancers, which overcome multiple fail-safe genetic controls.
From the viewpoint of TGF-β signaling, a key therapeutic aim in cancer would be restoration of the lost tumor suppressor function observed in normal hepatocytes at the expense of effects promoting aggressive behavior in HCC. Our model suggests that specific inhibitors of the pSmad3L-mediated oncogenic/fibrogenic signaling should inhibit progression of HCC.