Heparin-binding epidermal growth factor-like growth factor: a hepatic stellate cell proliferation inducer via ErbB receptors.

BACKGROUND AND AIM

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has a proliferative effect on several types of cells. However, the role of HB-EGF on hepatic stellate cells (HSCs) is not clear. The present study is to investigate the regulatory effects of HB-EGF on HSC proliferation and apoptosis.

METHODS

Activated primary rat HSCs and two HSC cell lines (human LX2 and rat T6) were used in this study. Four inhibitors (CRM197 to HB-EGF, AG1478 to epidermal growth factor receptor [EGFR], PD98059 to mitogen-activated kinase, and LY294002 to phosphatidylinositol 3-kinase) were employed to verify the pathway of HB-EGF on cell proliferation and apoptosis.

RESULTS

HB-EGF expression was significantly increased in activated HSCs. HB-EGF increased the expressions of phospho-EGFR and ErbB4 receptors, the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt. Consequently, HB-EGF stimulated HSC proliferation and suppressed HSC apoptosis. Each individual inhibitor specifically inhibited the correlated receptor or enzyme and inhibited HSC proliferation and induced its apoptosis.

CONCLUSIONS

HB-EGF promotes HSC proliferation via activation of the EGFR and ErbB4 receptors and, subsequently, via activation of ERK and Akt. Any blockage in the chain obstructs the flow from HB-EGF to HSC proliferation. Therefore, HB-EGF is a potential therapeutic target in liver fibrosis.