Hepatocyte growth factor-induced proliferation of hepatic stem-like cells depends on activation of NF-κB

Background/Aims Hepatocyte growth factor (HGF) regulates proliferation of hepatic stem cells. Transcription factor nuclear factor kappa B (NF-κB) has been demonstrated as a key mediator for cell growth regulation. We investigated the role of NF-κB in HGF-mediated cellular proliferation responses in a rat liver-derived hepatic stem-like cell line WB-F344. Methods Cell proliferation was determined by incorporation of [3H]thymidine. Phosphorylation of ERK1/2, p38 MAPK, Akt and IκBα by HGF stimulation was detected by Western blotting. NF-κB activation was determined by electrophoretic mobility shift assay and NF-κB-mediated SEAP reporter assay. NF-κB activation was inhibited by treatment with an IκBα dominant-negative vector or inhibitor BAY-11-7082. Results We found that stimulation of WB-F344 cells with HGF promoted cell proliferation and effectively protected WB-F344 cells from apoptosis induced by TNF-α. We also observed activation of ERK1/2, p38 MAPK, Akt and NF-κB signaling pathways by HGF in WB-F344 cells. HGF-induced cell proliferation was partly blocked by pre-treatment of the cells with inhibitors against MEK1 or p38 MAPK, and completely blocked using an inhibitor for NF-κB activity. Furthermore, it was demonstrated that IκB mutant that suppressed NF-κB activity completely blocked HGF-induced cell proliferation. Conclusions NF-κB activity is required for HGF-induced proliferation in hepatic stem-like cell line WB-F344, and this activity requires ERK1/2 and p38 MAPK pathways