Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocyte-specific gp130 knockout mice (gp130Δhepa) and control animals (gp130f/f) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0–144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130Δhepa animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130Δhepa mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130f/f and gp130Δhepa animals. However, gp130Δhepa livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-β (TGFβ), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC.

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and cigarette smoking. Contrarily, coffee consumption was identified to inversely correlate with the risk for HCC. In a recent meta-analysis of 10 studies (2,260 HCC cases), a 41% reduction in the risk of HCC among coffee drinkers compared with never-drinkers was reported. 13 Many patients with chronic hepatitis C use complementary and alternative medications, and some clinical trials have shown that herbal products may have therapeutic potential.In a systemic review from 2003, 13 randomized trials with a total of 818 patients and 14 different herbs including silymarin and glycyrrhizin were analyzed. 14 In some trials, HCV RNA decline and ALT normalization was observed; however, there was no firm evidence supporting herbal products for chronic hepatitis C. In a substudy from the HALT-C trial, the use and potential effects of silymarin was examined. 15 About 17% of the HALT-C trial population concomitantly took silymarin at baseline of the trial. No benefit on HCV RNA or ALT levels were found; however, silymarin users had fewer symptoms and better quality-of-life indices as nonusers.The most promising improvements for patients with chronic hepatitis C include the development of direct antivirals such as HCV protease and polymerase inhibitors. 16,17 Two protease inhibitors (telaprevir and boceprevir) are currently undergoing phase III clinical trials. In the future, safety and efficacy studies of these new compounds in the setting of advanced chronic hepatitis C will be necessary. AbstractInflammatory hepatocellular adenomas are benign liver tumours defined by the presence of inflammatory infiltrates and by the increased expression of inflammatory proteins in tumour hepatocytes. Here we show a marked activation of the interleukin (IL)-6 signalling pathway in this tumour type; sequencing candidate genes pinpointed this response to somatic gain-of-function mutations in the IL6ST gene, which encodes the signalling co-receptor gp130. Indeed, 60% of inflammatory hepatocellular adenomas

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