Stärkel Peter, Saeger Christine De, Leclercq Isabelle, Horsmans Yves
Department and Laboratory of Gastroenterology, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.
Lab Invest. 2007 Feb;87(2):173-81. doi: 10.1038/labinvest.3700496. Epub 2006 Nov 27.
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.
体外和动物实验数据表明，丙型肝炎病毒（HCV）蛋白可能会干扰信号转导和转录激活因子3（Stat3）信号通路。目前尚不清楚Stat3是否会影响凋亡-增殖平衡，以及这与HCV感染患者肝纤维化进展之间的关系。我们评估了65例处于不同纤维化进展阶段的HCV感染肝脏中Stat3的表达、DNA结合情况，以及其调节因子活化Stat 3蛋白抑制剂（Pias3）和细胞因子信号转导抑制因子3（Socs3）的表达。然后，我们在相同的肝脏样本中，结合细胞增殖标记物细胞周期蛋白D1和增殖细胞核抗原（PCNA）以及促凋亡和抗凋亡标记物Bax和Bcl-2，测定了它们的表达水平。随着纤维化的出现，Stat3的DNA结合能力下降，在出现桥接纤维化或肝硬化的肝脏中几乎检测不到。Stat3的DNA结合能力与Pias3的表达呈负相关，且Stat3与Pias3的相互作用随着纤维化的进展而增加。在纤维化进展过程中，肝细胞中的细胞周期蛋白D1和PCNA显著减少，其水平与Stat3的表达高度相关。此外，随着纤维化的进展，主要在浸润性炎症细胞中观察到由于Bcl-2上调导致的抗凋亡特征。总之，纤维化进展的特征是Stat3的DNA结合活性持续下降，这与Pias3-Stat3的过表达和逐渐相互作用有关。Stat3活性的降低与肝细胞增殖减少以及浸润性炎症细胞中抗凋亡平衡增强相关，而浸润性炎症细胞是HCV中已知的细胞损伤介质。
