Activation of ETA Receptor by Endothelin-1 Induces Hepatocellular Carcinoma Cell Migration and Invasion via ERK1/2 and AKT Signaling Pathways

Endothelin-1 (ET-1), a member of endothelins family, binds to ETA receptor (ETAR) and ETB receptor to exert its role in multiple cellular processes. Although ET-1 and its receptors has been reported to be overexpressed in many cancers, and overexpression of ET-1 is able to trigger hepatocarcinogenesis in zebrafish, the functions of ET-1 and its receptors in hepatocellular carcinoma (HCC) cell migration and invasion remain unclear. In the present study, we found that ETAR was greatly expressed in HCC cells and HCC tissues. ETAR expression as well as ET-1 expression was associated with vascular invasion and tumor stage in HCC. Activation of ETAR by ET-1 dose-dependently promoted cell migration and invasion of HCC cells, while silencing of ETAR by siRNA or blocking of ETAR by specific inhibitor resulted in significant reduction in ET-1-mediated migration and invasion. Furthermore, ET-1 induced activation of ERK1/2 and AKT and increased MMP-3 production via ETAR. In addition, using inhibitors of ERK1/2 and AKT, we found that ERK1/2 and AKT pathways were both involved in ETAR-mediated migration, invasion, and MMP-3 production. Taken together, our findings suggest that activation of ETAR by ET-1 promotes HCC cell migration and invasion via activating ERK1/2 and AKT signaling pathways and upregulating MMP-3 expression. Thus, ETAR may play an important role in the progress of HCC.