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.
OBJECTIVE
In vitro and animal data suggest that alcohol and hepatitis C virus (HCV) proteins might interfere with Stat3 signaling, a potential regulator of liver cell apoptosis and proliferation.


METHODS
We assessed Stat3 expression, activity and the apoptotic-proliferation balance in end-stage HCV and alcoholic liver disease (ALD) in man. Explanted livers of HCV and ALD patients were compared to normal and primary biliary cirrhosis (PBC) livers.


RESULTS
Although Stat3 expression and phosphorylation was not altered in HCV and ALD cirrhosis, Stat3 DNA-binding was not detected in all ALD and most HCV samples. Deficient Stat3 DNA-binding was associated with high Pias3 expression, but not with increased Socs3 levels. Bcl-2 was up-regulated in HCV and ALD together with decreased Caspase3 activity. Compared to base-line cell proliferation in normal donor livers, HCV cirrhosis showed a marked reduction in cyclin D1 and PCNA, whereas both markers were only slightly reduced in ALD.


CONCLUSIONS
End-stage HCV and ALD cirrhosis is characterized by impaired Stat3 DNA-binding possibly through up-regulation of Pias3. Therefore, impaired activation of Stat3 target genes might contribute to disturbed liver regeneration and repair. The attempt in cirrhotic livers to favor anti-apoptotic over pro-apoptotic pathways is not sufficient to compensate for the low cellular proliferation rates.
Stärkel
Peter
P
Department and Laboratory of Gastroenterology, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. peter.starkel@gaen.ucl.ac.be
De Saeger
Christine
C
Leclercq
Isabelle
I
Strain
Alastair
A
Horsmans
Yves
Y
D017209:Apoptosis / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006526:Hepatitis C / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology / Q000601:surgery / Q000821:virology; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D016031:Liver Transplantation; D018832:Molecular Chaperones / Q000235:genetics*; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics*
D004268:DNA-Binding Proteins; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT