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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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Disruption of gp130 in hepatocytes in females attenuates HCC progression. Gp130f/f and gp130Δhepa female 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, upper panel). H&E staining was performed from the same livers and photographed at different magnifications (left and right panels). (b, c) The number of nodules and the tumor area were determined by an experienced pathologist in a blinded session and represented. Tumor area was calculated as the percentage of total. Data are expressed as mean±SEM (n=6; *P<0.05; **P<0.01).
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fig5: Disruption of gp130 in hepatocytes in females attenuates HCC progression. Gp130f/f and gp130Δhepa female 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, upper panel). H&E staining was performed from the same livers and photographed at different magnifications (left and right panels). (b, c) The number of nodules and the tumor area were determined by an experienced pathologist in a blinded session and represented. Tumor area was calculated as the percentage of total. Data are expressed as mean±SEM (n=6; *P<0.05; **P<0.01).

Mentions: To determine whether the previously reported gender bias in IL-6 production that accounts for the sex difference in HCC development in these animals,14 we examined DEN-induced carcinogenesis in female gp130f/f and gp130Δhepa livers, 40 weeks after DEN treatment. Macroscopical examination of liver specimens manifested smaller nodules in gp130Δhepa compared with gp130f/f female mice (Figure 5a, upper panel). Further examination of H&E showed presence of visible HCC areas in gp130f/f female mice (Figure 5a, left panel). In contrast, gp130Δhepa female livers displayed normal liver architecture with the presence of some preneoplastic cells (Figure 5a, right panel). Consistent with these findings, there was a tendency for a reduction in the number of tumors (P=0.21) and the tumor fraction (P=0.09) in gp130Δhepa compared with gp130f/f females, 40 weeks after DEN (Figure 5b and c). Therefore, from these results, we cannot exclude the possibility that besides IL-6 other factors may also contribute to gender disparity in liver cancer.


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)

Disruption of gp130 in hepatocytes in females attenuates HCC progression. Gp130f/f and gp130Δhepa female 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, upper panel). H&E staining was performed from the same livers and photographed at different magnifications (left and right panels). (b, c) The number of nodules and the tumor area were determined by an experienced pathologist in a blinded session and represented. Tumor area was calculated as the percentage of total. Data are expressed as mean±SEM (n=6; *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

fig5: Disruption of gp130 in hepatocytes in females attenuates HCC progression. Gp130f/f and gp130Δhepa female 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, upper panel). H&E staining was performed from the same livers and photographed at different magnifications (left and right panels). (b, c) The number of nodules and the tumor area were determined by an experienced pathologist in a blinded session and represented. Tumor area was calculated as the percentage of total. Data are expressed as mean±SEM (n=6; *P<0.05; **P<0.01).
Mentions: To determine whether the previously reported gender bias in IL-6 production that accounts for the sex difference in HCC development in these animals,14 we examined DEN-induced carcinogenesis in female gp130f/f and gp130Δhepa livers, 40 weeks after DEN treatment. Macroscopical examination of liver specimens manifested smaller nodules in gp130Δhepa compared with gp130f/f female mice (Figure 5a, upper panel). Further examination of H&E showed presence of visible HCC areas in gp130f/f female mice (Figure 5a, left panel). In contrast, gp130Δhepa female livers displayed normal liver architecture with the presence of some preneoplastic cells (Figure 5a, right panel). Consistent with these findings, there was a tendency for a reduction in the number of tumors (P=0.21) and the tumor fraction (P=0.09) in gp130Δhepa compared with gp130f/f females, 40 weeks after DEN (Figure 5b and c). Therefore, from these results, we cannot exclude the possibility that besides IL-6 other factors may also contribute to gender disparity in liver cancer.

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