Soluble Egg Antigens of Schistosoma japonicum Induce Senescence of Activated Hepatic Stellate Cells by Activation of the FoxO3a/SKP2/P27 Pathway.
Soluble Egg Antigens of Schistosoma japonicum Induce Senescence of Activated Hepatic Stellate Cells by Activation of the FoxO3a/SKP2/P27 Pathway.
复制标题
日本血吸虫可溶性卵抗原通过激活 FoxO3a/SKP2/P27 通路诱导激活的肝星状细胞衰老
DOI：
10.1371/journal.pntd.0005268
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发表时间：
2016-12
影响因子：
3.8
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Duan Y;Pan J;Chen J;Zhu D;Wang J;Sun X;Chen L;Wu L
研究背景肝纤维化被认为是一个可逆的过程。肝星状细胞（hepatic stellate cells，HSC）的活化是肝纤维化过程中的关键事件。诱导HSC衰老可加速活化HSC的清除。日本血吸虫可溶性虫卵抗原（SEA）通过STAT 3/P53/P21途径促进HSC的衰老。本研究旨在探讨SEA诱导HSC衰老过程中是否存在其他信号通路，以及SKP 2/P27信号在衰老HSC中的作用。方法/主要发现人肝星状细胞系LX-2细胞，培养和刺激SEA。Western blot和细胞免疫荧光分析检测衰老相关蛋白P27、SKP 2和FoxO 3a的表达。此外，还应用RNA干扰技术敲低相关蛋白的表达。通过衰老相关β-gal染色确定HSC的衰老。结果表明，SEA能促进P27蛋白的表达，而抑制SKP 2和FoxO 3a的表达。P27的敲除以及SKP 2的过表达均抑制SEA诱导的HSC衰老。此外，SEA刺激诱导FoxO 3a从细胞核到细胞质的核转位。结论SEA通过FoxO 3a/SKP 2/P27途径促进HSC的衰老。
Background Liver fibrosis was viewed as a reversible process. The activation of hepatic stellate cells (HSCs) is a key event in the process of liver fibrosis. The induction of senescence of HSCs would accelerate the clearance of the activated HSCs. Previously, we demonstrated that soluble egg antigens (SEA) of Schistosoma japonicum promoted the senescence of HSCs via STAT3/P53/P21 pathway. In this paper, our study was aimed to explore whether there are other signaling pathways in the process of SEA-induced HSCs aging and the underlying effect of SKP2/P27 signal on senescent HSCs. Methodology/Principal findings Human hepatic stellate cell line, LX-2 cells, were cultured and stimulated with SEA. Western blot and cellular immunofluorescence analysis were performed to determine the expression of senescence-associated protein, such as P27, SKP2 and FoxO3a. Besides, RNA interfering was applied to knockdown the expression of related protein. The senescence of HSCs was determined by senescence-associated β-gal staining. We found that SEA increased the expression of P27 protein, whereas it inhibited the expression of SKP2 and FoxO3a. Knockdown of P27 as well as overexpression of SKP2 both suppressed the SEA-induced senescence of HSCs. In addition, the nuclear translocation of FoxO3a from the nucleus to the cytoplasm was induced by SEA stimulation. Conclusions/Significance The present study demonstrates that SEA promotes HSCs senescence through the FoxO3a/SKP2/P27 pathway.