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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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Oxidative stress plays an important role in liver injury after DEN treatment. (a) RNA was extracted from total liver lysates 40 weeks after DEN treatment and qRT PCR for BRCA-1 was performed. (b) Quantification of the pH2AX immunostaining of liver sections for pH2AX of gp130Δhepa and gp130f/f mice 40 weeks after DEN treatment is shown. Vehicle (saline) injected animals of both genotypes were used as controls. (c) Representative immunofluorescence of liver sections for dihydroethidium (DHE) of gp130Δhepa and gp130f/f mice 40 weeks after DEN treatment was assessed. Vehicle-injected animals of both genotypes served as controls. (d) Quantitative measurement of malondialdehyde (MDA) from total liver lysates of the same mice. Vehicle-injected animals of both genotypes served as controls. Data are expressed as mean+SEM (n=5; **P<0.01).
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fig6: Oxidative stress plays an important role in liver injury after DEN treatment. (a) RNA was extracted from total liver lysates 40 weeks after DEN treatment and qRT PCR for BRCA-1 was performed. (b) Quantification of the pH2AX immunostaining of liver sections for pH2AX of gp130Δhepa and gp130f/f mice 40 weeks after DEN treatment is shown. Vehicle (saline) injected animals of both genotypes were used as controls. (c) Representative immunofluorescence of liver sections for dihydroethidium (DHE) of gp130Δhepa and gp130f/f mice 40 weeks after DEN treatment was assessed. Vehicle-injected animals of both genotypes served as controls. (d) Quantitative measurement of malondialdehyde (MDA) from total liver lysates of the same mice. Vehicle-injected animals of both genotypes served as controls. Data are expressed as mean+SEM (n=5; **P<0.01).

Mentions: Maintenance of genome stability after DNA damage depends on BRCA1.23 We observed that 40 weeks after DEN administration BRCA1 mRNA expression was significantly elevated in DEN-induced gp130f/f tumor tissue compared with gp130Δhepa livers, suggesting a reduced amount of DNA double-strand breaks in gp130Δhepa livers (Figure 6a). This was associated with a tendency toward reduced levels of pH2AX in gp130Δhepa livers, 40 weeks after DEN treatment, although the observed differences did not reach statistical significance (Figure 6b).


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)

Oxidative stress plays an important role in liver injury after DEN treatment. (a) RNA was extracted from total liver lysates 40 weeks after DEN treatment and qRT PCR for BRCA-1 was performed. (b) Quantification of the pH2AX immunostaining of liver sections for pH2AX of gp130Δhepa and gp130f/f mice 40 weeks after DEN treatment is shown. Vehicle (saline) injected animals of both genotypes were used as controls. (c) Representative immunofluorescence of liver sections for dihydroethidium (DHE) of gp130Δhepa and gp130f/f mice 40 weeks after DEN treatment was assessed. Vehicle-injected animals of both genotypes served as controls. (d) Quantitative measurement of malondialdehyde (MDA) from total liver lysates of the same mice. Vehicle-injected animals of both genotypes served as controls. Data are expressed as mean+SEM (n=5; **P<0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: Oxidative stress plays an important role in liver injury after DEN treatment. (a) RNA was extracted from total liver lysates 40 weeks after DEN treatment and qRT PCR for BRCA-1 was performed. (b) Quantification of the pH2AX immunostaining of liver sections for pH2AX of gp130Δhepa and gp130f/f mice 40 weeks after DEN treatment is shown. Vehicle (saline) injected animals of both genotypes were used as controls. (c) Representative immunofluorescence of liver sections for dihydroethidium (DHE) of gp130Δhepa and gp130f/f mice 40 weeks after DEN treatment was assessed. Vehicle-injected animals of both genotypes served as controls. (d) Quantitative measurement of malondialdehyde (MDA) from total liver lysates of the same mice. Vehicle-injected animals of both genotypes served as controls. Data are expressed as mean+SEM (n=5; **P<0.01).
Mentions: Maintenance of genome stability after DNA damage depends on BRCA1.23 We observed that 40 weeks after DEN administration BRCA1 mRNA expression was significantly elevated in DEN-induced gp130f/f tumor tissue compared with gp130Δhepa livers, suggesting a reduced amount of DNA double-strand breaks in gp130Δhepa livers (Figure 6a). This was associated with a tendency toward reduced levels of pH2AX in gp130Δhepa livers, 40 weeks after DEN treatment, although the observed differences did not reach statistical significance (Figure 6b).

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