Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model.
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 (gp130(Δhepa)) and control animals (gp130(f/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 gp130(Δhepa) 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 gp130(Δhepa) 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 gp130(f/f) and gp130(Δhepa) animals. However, gp130(Δhepa) 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.
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
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Hatting
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
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M
Spannbauer
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
J
J
Peng
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
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M
Al Masaoudi
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
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G
Sellge
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
Y A
YA
Nevzorova
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
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N
Gassler
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
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C
Liedtke
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
F J
FJ
Cubero
Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
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C
Trautwein
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004052:Diethylnitrosamine / Q000633:toxicity; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053683:Oncostatin M / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism
D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D053683:Oncostatin M; D050822:Cytokine Receptor gp130; D004052:Diethylnitrosamine