Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model

Abstract

Background & Aim: Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that IL-6/gp130-dependent signaling plays 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. Methods: Hepatocyte-specific gp130 knockout mice (gp130Δhepa) and control animals (gp130f/f) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0 – 5 days), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. Results: After acute DEN-induced liver injury we observed a reduction in the inflammatory response as reflected by decreased IL-6 and oncostatin M (OSM) levels in gp130Δhepa animals. Loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN-induced tumor initiation. In contrast, 40 weeks after DEN treatment, gp130Δhepa livers displayed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. We found increased oxidative stress and substantial DNA damage in animals after DEN injection, but no significant difference between gp130f/f and gp130Δhepa animals. However, while STAT3 phosphorylation was absent in gp130Δhepa hepatocytes we found STAT5 activation and decreased TGFβ-dependent activity in these livers. Conclusion: 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 TGFβ-dependent signaling. Hence, blocking gp130 in hepatocytes is an interesting therapeutic target to inhibit the growth of HCC.