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

Hatting M, Spannbauer M, Peng J, Al Masaoudi M, Sellge G, Nevzorova YA, Gassler N, Liedtke C, Cubero FJ, Trautwein C - Cell Death Dis (2015)

Bottom Line: 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.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.Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.

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 (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.

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Gp130 in hepatocytes contributes to tumor progression in the DEN model. In the presence of gp130 in hepatocytes, DEN induces IL-6 and OSM signaling through gp130 activating STAT3, TGFb-dependent pathways and HCC progression. The absence of gp130 in hepatocytes results in decreased IL-6 and OSM signaling and constitutive phosphorylation of STAT5 occurs, which impairs TGFb-dependent mechanisms, thus attenuating HCC development.
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fig8: Gp130 in hepatocytes contributes to tumor progression in the DEN model. In the presence of gp130 in hepatocytes, DEN induces IL-6 and OSM signaling through gp130 activating STAT3, TGFb-dependent pathways and HCC progression. The absence of gp130 in hepatocytes results in decreased IL-6 and OSM signaling and constitutive phosphorylation of STAT5 occurs, which impairs TGFb-dependent mechanisms, thus attenuating HCC development.

Mentions: We conclude that gp130 in hepatocytes contributes to tumor progression but not to tumor initiation in the DEN model. In the presence of gp130 in hepatocytes, DEN induces IL-6 and OSM signaling through gp130-activating STAT3, TGFβ-dependent pathways and HCC progression. Conversely, the absence of gp130 in hepatocytes results in decreased IL-6 and OSM expression, constitutive phosphorylation of STAT5 and subsequently impaired TGFβ-dependent signaling, thereby attenuating HCC development (Figure 8). Thus, gp130 in hepatocytes seems an interesting therapeutic target for blocking progression of HCC.


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

Hatting M, Spannbauer M, Peng J, Al Masaoudi M, Sellge G, Nevzorova YA, Gassler N, Liedtke C, Cubero FJ, Trautwein C - Cell Death Dis (2015)

Gp130 in hepatocytes contributes to tumor progression in the DEN model. In the presence of gp130 in hepatocytes, DEN induces IL-6 and OSM signaling through gp130 activating STAT3, TGFb-dependent pathways and HCC progression. The absence of gp130 in hepatocytes results in decreased IL-6 and OSM signaling and constitutive phosphorylation of STAT5 occurs, which impairs TGFb-dependent mechanisms, thus attenuating HCC development.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4385909&req=5

fig8: Gp130 in hepatocytes contributes to tumor progression in the DEN model. In the presence of gp130 in hepatocytes, DEN induces IL-6 and OSM signaling through gp130 activating STAT3, TGFb-dependent pathways and HCC progression. The absence of gp130 in hepatocytes results in decreased IL-6 and OSM signaling and constitutive phosphorylation of STAT5 occurs, which impairs TGFb-dependent mechanisms, thus attenuating HCC development.
Mentions: We conclude that gp130 in hepatocytes contributes to tumor progression but not to tumor initiation in the DEN model. In the presence of gp130 in hepatocytes, DEN induces IL-6 and OSM signaling through gp130-activating STAT3, TGFβ-dependent pathways and HCC progression. Conversely, the absence of gp130 in hepatocytes results in decreased IL-6 and OSM expression, constitutive phosphorylation of STAT5 and subsequently impaired TGFβ-dependent signaling, thereby attenuating HCC development (Figure 8). Thus, gp130 in hepatocytes seems an interesting therapeutic target for blocking progression of HCC.

Bottom Line: 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.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.Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.

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 (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.

Show MeSH
Related in: MedlinePlus