In many tumor types, selleck products NF-κB is highly activated and often addictive (inactivation leads to cell death or tumor remission).8 In liver, NF-κB activation in NPCs is necessary for HCC tumor promotion,9 whereas its function in hepatocytes

is prosurvival and induces protumor cytokines including IL-6 and TNF-α.10 STAT3 can function as a driver oncogene and has been shown, along with IL-6, to be part of an epigenetic switch established during transformation.11 Overlap in the transcriptional regulatory network between inflammation and transformation has been demonstrated in other tumor models, suggesting inflammation-driven signaling within preneoplastic cells can cooperate or contribute directly to oncogenic transformation.11 With regard to hepatocellular transformation, constitutive selleckchem activating mutations in both gp130 (IL-6 signal transducer) and STAT3 have been demonstrated in more than 70% of inflammatory hepatocellular adenomas.12 Furthermore, isolated human HCC stem cells are marked by high expression of IL-6 and STAT3, but often also with loss of the type 2 TGF-β receptor (TGFBR2). This suggests that IL-6 autocrine signaling may be more important than maintaining TGF-β signaling in driving transformed stem

cells toward HCC.13 TGF-β plays a complex role, depending on the context and stage of the “fibrosis-cirrhosis-HCC” process.9 A recent study revealed inactivation of TGF-β signaling through deletion of TGFBR2 Inositol oxygenase reduced HCC formation caused by p53 loss in albumin-cre transgenic mice.13 In contrast, Ozturk’s group found that TGF-β treatment in vitro induced growth inhibition in well-differentiated HCC cell lines that have p53 mutations and express TGFBR2.14 The results of their analysis of TGF-β expression in normal, cirrhotic, and HCC liver, using publicly available clinical data, showed that TGF-β was sharply increased in patients with liver cirrhosis, but was followed by a significant decrease

in patients with early or advanced HCC. Furthermore, TGFBR2 is also reported to be down-regulated in 37%-70% of patients with HCC.13 These paradoxical findings may be reconciled by recognizing that the roles of TGF-β in HCC tumorigenesis are inherently different at various stages of disease development. In cirrhotic liver, up-regulated TGF-β promotes the transformation and growth of neoplastic cells with existing p53 mutations, whereas after tumor development, HCC cells may escape growth inhibition possibly by down-regulating their TGF-β receptors and “instructing” the microenvironment to shut down the expression of TGF-β. Stage-dependent TGF-β signaling is also influenced by differential cytokine-activated-kinase phosphorylation of Smad proteins. Normally, TGF-β-mediated Smad3 signaling terminates hepatocyte proliferation during acute liver injury.