Abstract
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.
Highlights
The driving pathophysiological mechanisms by which tumor initiation and progression occur during the process of hepatic carcinogenesis needs to be explored to target pathways, which are attractive for therapeutic intervention
We aimed to investigate the role of gp[130] in hepatocytes for the initiation and progression of Hepatocellular carcinoma (HCC) during inflammation-triggered carcinogenesis
FACS analysis showed significantly reduced infiltration of polymorphonuclear neutrophil (PMN) and a tendency for a decreased number of inflammatory monocytes in livers of gp130Δhepa compared with gp130f/f animals 72 h after DEN treatment (Figure 1b and c), whereas the numbers of hepatic T, B, and NK cells were unchanged (Supplementary Figure 2a and c)
Summary
Hepatocellular carcinoma (HCC) represents a major health problem as it ranks fifth among the solid tumors and third among the worldwide cause of cancer mortality in males with half a million deaths per year.[1,2] The development of HCC is a multifactorial process that includes the accumulation of mutations in the cellular tumor-suppressive and tumorpromoting pathways as well as a disturbance in immune surveillance. It involves the transition of a normal cell to a preneoplastic lesion that develops into a malignant tumor. Gp130 has been shown to have a fundamental role in the development, hematopoiesis, cell survival and growth as well as in infection, immunity and inflammation.[3,6] Especially, molecular studies of IL-6 dependent gp[130] activation have significantly contributed to the understanding of the role of gp[130] during infection and inflammation.[7]
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