TGF-β and hepatocellular carcinoma
Authors: Marina Bortolami, Romilda Cardin, Andromachi Kotsafti, Fabio Farinati
Journal: Hepatology (2008)

We read with interest the article by Matsuzaki et al.1 that elegantly describes one of the many possible pathways along which transforming growth factor-β (TGF-β) expression may influence damage progression, and eventually carcinogenesis, in chronic hepatitis. The authors suggest that chronic inflammation associated with hepatitis C virus infection (HCV) hijacks TGF-β signaling from tumor-suppression to fibrogenesis in the liver, consequently accelerating liver fibrosis and increasing the development of hepatocellular carcinoma (HCC). The most impressive finding of the study is indeed the very high risk of neoplastic evolution in patients with increased phosphorylation at linker region of Small Body Size 3 protein (pSMAD3L). The constitutive Smad3L phosphorylation in cirrhosis and HCC was shown to be at least in part boosted by interleukin-1 beta (IL-1β), the direct consequence of the event being an increase in the amount of pSmad3L available for fibrogenic action in hepatocytes, and in the meantime a down-regulation of TGF-β-dependent tumor-suppressive activity. TGF-β acts indeed as a tumor suppressor, and one of the mechanisms involved is induction of apoptosis. This has been recently confirmed by Zhang et al.,2 who showed a TGF-β–dependent accumulation of programmed cell death 4 (PDCD4) proteins in the nuclei of human hepatoma Huh7 cells, in parallel with increased apoptosis, as demonstrated by terminal uridine deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. That TGF-β induces apoptosis in human HCC cell lines was already known, but this study highlights one of the possible mechanisms underlying this effect. With respect to SMAD3, this transcriptional activator has been also shown to modulate hepatocyte apoptosis through generation of reactive oxygen species.3 We are very interested in this last aspect, and we thought it might be constructive for the discussion to briefly report some of our data on the topic. We recently obtained results in patients with HCV-mediated hepatitis, cirrhosis, and HCC that show an interesting correlation of TGF-β levels with 8-hydroxydeoxyguanosine (8OHdG) (P = 0.05), a reliable marker of oxidative DNA damage, and with both Bcl-2 and Bax transcript tissue levels, as ascertained by quantitative real-time polymerase chain reaction analysis (P = 0.01 and P = 0.007, respectively). Additionally, in cirrhosis, both IL-1β and DNA oxidative damage levels were sharply increased.4, 5 The correlation with both proapoptotic and antiapoptotic mediators with TGF-β is somewhat surprising and intriguing, but it must be kept in mind that the overexpression of Bcl-2 may correspond to an inhibitory effect on apoptotic cell death but also may have the ability of enhancing apoptosis through the interaction of Bcl-XL with other factors such as Bax and Bak.6 Overall, inflammation, free radical production, TGF-β, and TGF-β–mediated down-stream effects on SMAD, PCDC4, and apoptotic mediators (Bcl-2 and Bax) are deeply involved in damage progression during chronic hepatitis, as well as in liver carcinogenesis. Therefore, as suggested by the Matsuzaki et al., specific inhibitors of the TGF-β–dependent pathways could be used to suppress progression of both liver fibrosis and cancer. Marina Bortolami*, Romilda Cardin*, Andromachi Kotsafti*, Fabio Farinati*, * University of Padua, Department of Surgical and Gastroenterological Sciences, Padua, Italy.