TWEAK promotes hepatic stellate cell migration through activating EGFR/Src and PI3K/AKT pathways

Activated human hepatic stellate cells (HSCs) showed enhanced ability of migration compared with quiescent HSCs, which is pivotal in liver fibrogenesis. The aim of the present study was to investigate the effects of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) on the migration of activated HSCs and to explore the relevant potential mechanisms. Human HSCs LX-2 cells were cultured with TWEAK. TNFRSF12A-downexpressing lentiviruses were used to infect LX-2 cells. The specific matrix metalloproteinases inhibitor BB94, the Src family kinase inhibitor, Dasatinib, and the specific inhibitor of phosphoinositide 3-kinase (PI3K), LY294002 were used to treat LX-2 cells combined with TWEAK. Cell migration and invasion was tested by the transwell assay. The expression of EGFR/Src, PI3K/AKT, and matrix metallopeptidase 9 (MMP9) was identified by real-time polymerase chain reaction or western blotting. The result showed TWEAK promoted HSC migration and collagen production. BB94 significantly attenuated the migration of LX-2 induced by TWEAK. Dasatinib inhibited the ability of cell migration stimulated by TWEAK. TWEAK upregulated the phosphorylation of epidermal growth factor receptor (EGFR) and Src. The phosphorylation of PI3K and AKT was significantly activated by TWEAK stimulation. Inhibition of PI3K/AKT reduced the expression of MMP9 induced by TWEAK. The present study, for the first time, demonstrated that TWEAK promoted HSC migration through the activation of EGFR/Src and PI3K/AKT pathways, and showed a novel potential mechanism of HSC migration regulated by TWEAK.