Abstract
BackgroundLiver 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 findingsHuman 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/SignificanceThe present study demonstrates that SEA promotes HSCs senescence through the FoxO3a/SKP2/P27 pathway.
Highlights
Liver fibrosis, a major health problem worldwide [1], results from different etiologies of chronic liver injury, and eventually progresses into cirrhosis or hepatocellular carcinoma
The present study demonstrates that soluble egg antigens (SEA) promotes hepatic stellate cells (HSCs) senescence through the FoxO3a/S phase kinase associated protein 2 (SKP2)/P27 pathway
Senescence of HSCs is mediated by exposure to soluble egg antigens (SEA) of Schistosoma japonicum via STAT3/P53/ P21 pathway
Summary
A major health problem worldwide [1], results from different etiologies of chronic liver injury, and eventually progresses into cirrhosis or hepatocellular carcinoma. Studies indicate that the activation of hepatic stellate cells (HSCs) is a key event in the process of liver fibrosis. In the process of liver fibrosis induced by S. japonicum infection, HSCs gather around S. japonicum egg granuloma [5]. Activated HSCs can express a variety of inhibitors of metalloproteinases (TIMPs) to prevent the degradation of matrix proteins, resulting in the replacement of normal liver tissue by collagen matrix and the formation of fibrous scar. Inhibition of the HSCs activation, proliferation and accelerating the clearance of the activated HSCs are key strategies for the prevention and treatment of liver fibrosis [6]. The activation of hepatic stellate cells (HSCs) is a key event in the process of liver fibrosis. 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
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