Deficient Stat3 DNA-binding is associated with high Pias3 expression and a positive anti-apoptotic balance in human end-stage alcoholic and hepatitis C cirrhosis

Stärkel, Peter; Saeger, Christine De; Leclercq, Isabelle; Strain, Alastair J.; Horsmans, Yves

doi:10.1016/j.jhep.2005.03.024

Cited by 26 publications

(26 citation statements)

References 47 publications

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“…However, more samples are required to confirm the elevated STAT3 activation in the early stage of alcoholic liver injury. The underlying mechanisms by which STAT3 activation is suppressed in alcoholic cirrhosis compared to HCV cirrhosis are not clear and may be related to a direct inhibition by ethanol of STAT3 (Chen et al, 1997;Chen et al, 2001;Chen et al, 1999;Gao, 2004) and elevation of PIAS3 (an inhibitor for STAT3) expression in alcoholic cirrhosis (Starkel et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, ethanol inhibition of liver regeneration in rodents is mediated at least in part by impairing IL-6 activation of STAT3 in the liver. Starkel et al (2005) showed that STAT3 expression and phosphorylation was not altered in HCV and alcoholic cirrhosis, while STAT3 DNA-binding was not detected in all alcoholic and most HCV samples. Since whole liver tissues were used in their study, it was not possible to distinguish the cell type associated with altered STAT3 in these cirrhotic livers.…”

Section: Introductionmentioning

confidence: 89%

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Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation

Horiguchi¹,

Ishac²,

Gao³

2007

Alcohol

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Liver regeneration is suppressed in alcoholic patients; however, the underlying mechanisms are not fully understood. We examined liver regeneration and STAT3 activation (an important signal for liver regeneration) in cirrhotic livers from alcoholics, HCV infection, and alcoholic plus HCV infection. Liver regeneration and STAT3 activation were determined by immunohistochemistry analysis of Ki67 and STAT3 phosphorylation, respectively, in 20 alcoholic cirrhosis, 13 HCV cirrhosis, 13 alcoholic+HCV cirrhosis. Alcoholic or alcoholic plus HCV cirrhotic livers had significantly lower Ki67 + and pSTAT3 + hepatocytes and bile duct cells than HCV cirrhotic livers. The pSTAT3 positive staining did not correlate with liver injury (elevation of serum levels of aspartate transaminase (ALT) and alkaline phosphatase (ALP) but correlated positively with cell proliferation (Ki67 positive staining). In conclusion: Liver regeneration is suppressed in alcoholic cirrhotic livers, which may be partly due to decreased STAT3 activation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation

Horiguchi¹,

Ishac²,

Gao³

2007

Alcohol

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“…1,3,[25][26][27] Our group has also shown that Stat3 activity is altered in vivo in human alcoholic and HCV end-stage liver disease. 18,19 Although one can conclude from these observations that Stat3 activity is altered by infection with HCV, it remains to be established whether inhibition of Stat3 activity plays a role in disease progression in vivo in humans and how this alteration relates to the proliferation-apoptosis status in HCV liver samples with various levels of fibrosis. The present study shows that HCV in human liver samples in vivo, induces an alteration in Stat3 function that worsens with fibrosis progression leading to an almost complete Stat3 inhibition at the stage of cirrhosis.…”

Section: Fibrosis Progression In Hcv-infected Livers Is Associated Wimentioning

confidence: 99%

“…We previously reported that Stat3 activity is disturbed in human end-stage alcoholic and HCV-related cirrhosis. 18,19 It remains, however, to be investigated whether alterations in Stat3 activity occur gradually during disease progression and are implicated in the pathogenesis of HCV-related liver disease or whether they should only be considered as a by-stander of end-stage liver disease. In addition, the potential relationship between Stat3 alterations and cell proliferation or apoptosis has not been clarified in human liver.…”

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confidence: 99%

Role of signal transducer and activator of transcription 3 in liver fibrosis progression in chronic hepatitis C-infected patients

Stärkel

Saeger

Leclercq

et al. 2007

Laboratory Investigation

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In vitro and animal data suggest that hepatitis C virus (HCV) proteins might interfere with signal transducer and activator of transcription 3 (Stat3) signaling. It remains unknown whether Stat3 influences the apoptotic-proliferation balance and how this may relate to liver fibrosis progression in HCV-infected patients. We assessed Stat3 expression and DNA-binding as well as expression of its regulators protein inhibitor of activated Stat 3 (Pias3) and suppressor of cytokine signaling 3 (Socs3) in 65 HCV-infected livers at various stages of fibrosis progression. We then determined the level of expression of the proliferation markers cyclin D1 and proliferating cell nuclear antigen (PCNA) in conjunction with pro-and antiapoptotic markers Bax and Bcl-2 in the same liver samples. With the onset of fibrosis, Stat3 DNA-binding decreased and became almost undetectable in livers with bridging fibrosis or cirrhosis. Stat3 DNA-binding inversely correlated with Pias3 expression and Stat3-Pias3 interaction increased with the progression of fibrosis. Cyclin D1 and PCNA in hepatocytes decreased dramatically during fibrosis progression and levels highly correlated with Stat3 expression. In addition, an antiapoptotic profile due to upregulation of Bcl-2 principally in infiltrating inflammatory cells was observed with progressing fibrosis. In conclusion, fibrosis progression is characterized by a continuous decline in Stat3 DNA-binding activity related to overexpression and progressive interaction of Pias3-Stat3. The decrease in Stat3 activity correlated with reduced hepatocytes proliferation and a positive antiapoptotic balance in infiltrating inflammatory cells that are known mediators of cell damage in HCV.

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“…STAT3, a member of the JAK–STAT family, is also closely regulated by SOCS3, and disruption of STAT3-mediated intracellular signal transduction pathways could lead to disturbed liver regeneration and repair 21 – 24. Data in the literature suggest that HCV modulates STAT3 signalling,25 26 and in vivo studies in humans add further evidence that deficient STAT3 signalling does contribute to liver fibrosis progression in HCV-infected patients 27 28. It is conceivable that SNPs like those described by Persico et al in the SOCS3 gene lead to a wider range of functional consequences integrating blunted antiviral defence and inadequate liver repair in response to injury.…”

mentioning

confidence: 98%

Genetic factors predicting response to interferon treatment for viral hepatitis C

Stärkel

2007

Gut

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Deficient Stat3 DNA-binding is associated with high Pias3 expression and a positive anti-apoptotic balance in human end-stage alcoholic and hepatitis C cirrhosis

Cited by 26 publications

References 47 publications

Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation

Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation

Role of signal transducer and activator of transcription 3 in liver fibrosis progression in chronic hepatitis C-infected patients

Genetic factors predicting response to interferon treatment for viral hepatitis C

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