Role of signal transducer and activator of transcription 3 in liver fibrosis progression in chronic hepatitis C-infected patients.
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.
Stärkel
Peter
P
Department and Laboratory of Gastroenterology, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium. peter.starkel@gaen.ucl.ac.be
Saeger
Christine De
CD
Leclercq
Isabelle
I
Horsmans
Yves
Y
D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D017931:DNA Primers; D005786:Gene Expression Regulation; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D018832:Molecular Chaperones / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; D056741:Cyclin D; D016213:Cyclins; D017931:DNA Primers; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D018809:Proliferating Cell Nuclear Antigen; D050828:Protein Inhibitors of Activated STAT; D019253:Proto-Oncogene Proteins c-bcl-2; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051028:bcl-2-Associated X Protein; D004247:DNA