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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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Ablation of gp130 in hepatocytes reduces HCC progression in males. Male gp130f/f and gp130Δhepa mice were treated with a single i.p. DEN injection and killed 40 weeks later. (a) Representative macroscopic views of the livers are shown (dotted circles represent dysplastic nodules; left panel). H&E staining was performed from the same livers and photographed at different magnifications (center and right panel). (b) Tumors of randomly chosen H&E slides were counted by an experienced pathologist in a blinded session. Total area of the liver section was measured and results calculated as tumors per cm2 of liver section. (c) The total area of the section and the area of the tumor were measured. Tumor area was calculated as the percentage of total. Data are expressed as mean±SEM (n=5; *P<0.05; **P<0.01).
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fig4: Ablation of gp130 in hepatocytes reduces HCC progression in males. Male gp130f/f and gp130Δhepa mice were treated with a single i.p. DEN injection and killed 40 weeks later. (a) Representative macroscopic views of the livers are shown (dotted circles represent dysplastic nodules; left panel). H&E staining was performed from the same livers and photographed at different magnifications (center and right panel). (b) Tumors of randomly chosen H&E slides were counted by an experienced pathologist in a blinded session. Total area of the liver section was measured and results calculated as tumors per cm2 of liver section. (c) The total area of the section and the area of the tumor were measured. Tumor area was calculated as the percentage of total. Data are expressed as mean±SEM (n=5; *P<0.05; **P<0.01).

Mentions: After single low-dose DEN treatment, macroscopic HCC formation typically occurs between 35 and 52 weeks.22 We thus investigated tumor progression in male gp130f/f and gp130Δhepa livers 40 weeks after DEN injection (Figure 4). Macroscopically, tumor nodules were evident in both gp130f/f and gp130Δhepa livers (Figure 4a). However, the number of nodules and tumor fraction in gp130Δhepa livers was significantly reduced compared with gp130f/f animals at this time point (Figure 4a–c,Supplementary Figure 5a). Furthermore, these findings were associated with a reduction in tumor nodules on the surface of DEN-treated gp130Δhepa livers and a clear tendency in the cumulative diameter (Supplementary Figure 5b and c), whereas the liver versus body weight ratio did not show statistical difference between gp130Δhepa and gp130f/f mice (Supplementary Figure 5d). Consistent with these data, immunofluorescence staining of frozen tissue evidenced a tendency for reduction of CD11b+- cell infiltration and F4/80+-positive staining in gp130Δhepa compared with gp130f/f livers as a sign of tumor-associated inflammation, 40 weeks after DEN induction (Supplementary Figure 6a and b). Altogether our findings show that gp130 in hepatocytes is involved in HCC progression.


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)

Ablation of gp130 in hepatocytes reduces HCC progression in males. Male gp130f/f and gp130Δhepa mice were treated with a single i.p. DEN injection and killed 40 weeks later. (a) Representative macroscopic views of the livers are shown (dotted circles represent dysplastic nodules; left panel). H&E staining was performed from the same livers and photographed at different magnifications (center and right panel). (b) Tumors of randomly chosen H&E slides were counted by an experienced pathologist in a blinded session. Total area of the liver section was measured and results calculated as tumors per cm2 of liver section. (c) The total area of the section and the area of the tumor were measured. Tumor area was calculated as the percentage of total. Data are expressed as mean±SEM (n=5; *P<0.05; **P<0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Ablation of gp130 in hepatocytes reduces HCC progression in males. Male gp130f/f and gp130Δhepa mice were treated with a single i.p. DEN injection and killed 40 weeks later. (a) Representative macroscopic views of the livers are shown (dotted circles represent dysplastic nodules; left panel). H&E staining was performed from the same livers and photographed at different magnifications (center and right panel). (b) Tumors of randomly chosen H&E slides were counted by an experienced pathologist in a blinded session. Total area of the liver section was measured and results calculated as tumors per cm2 of liver section. (c) The total area of the section and the area of the tumor were measured. Tumor area was calculated as the percentage of total. Data are expressed as mean±SEM (n=5; *P<0.05; **P<0.01).
Mentions: After single low-dose DEN treatment, macroscopic HCC formation typically occurs between 35 and 52 weeks.22 We thus investigated tumor progression in male gp130f/f and gp130Δhepa livers 40 weeks after DEN injection (Figure 4). Macroscopically, tumor nodules were evident in both gp130f/f and gp130Δhepa livers (Figure 4a). However, the number of nodules and tumor fraction in gp130Δhepa livers was significantly reduced compared with gp130f/f animals at this time point (Figure 4a–c,Supplementary Figure 5a). Furthermore, these findings were associated with a reduction in tumor nodules on the surface of DEN-treated gp130Δhepa livers and a clear tendency in the cumulative diameter (Supplementary Figure 5b and c), whereas the liver versus body weight ratio did not show statistical difference between gp130Δhepa and gp130f/f mice (Supplementary Figure 5d). Consistent with these data, immunofluorescence staining of frozen tissue evidenced a tendency for reduction of CD11b+- cell infiltration and F4/80+-positive staining in gp130Δhepa compared with gp130f/f livers as a sign of tumor-associated inflammation, 40 weeks after DEN induction (Supplementary Figure 6a and b). Altogether our findings show that gp130 in hepatocytes is involved in HCC progression.

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