The Research On Regorafenib Resistance Mediated By HGF/c-Met/Snail/EMT Pathway In Hepatocellular Carcinoma

Objective:Hepatocellular carcinoma(HCC)is a fatal menace to human health due to its high morbidity and mortality.As a new second-line targeted therapy drug,regorafenib brings great benefits to patients with advanced HCC,but like sorafenib,drug resistance will also become a hard barrier to limiting its efficacy.In this research,we aimed to explore the underlying mechanisms of regorafenib resistance.Methods:Firstly,two HCC cell lines,MHCC-97H and BEL-7405,were continuously exposed to low concentrations of regorafenib.Regorafenib-resistant HCC cell lines were generated after eight weeks.Then the cell viability,invasive and migrative capacity of parental cells and resistant cells were compared.The resistant mechanisms were revealed by adopting siRNA and pathway inhibitorsResults:We found that continuous exposure induced regorafenib resistance in HCC cells.Regorafenib-resistant HCC cells showed mesenchymal phenotype,enhanced migration and invasion capabilities,increased Snail expression and occurrence of EMT While inhibition of Snail reversed the occurrence of EMT and regorafenib resistance.Further studies demonstrated that HGF/c-Met pathways was activated in regorafenib-resistant HCC cells.The inhibition of HGF/c-Met pathways by crizotinib reversed EMT mediated by up-regulation expression of Snail and regorafenib resistance.Conclusions:Continuous exposure with low concentration of regorafenib induced regorafenib resistance in HCC cells by activating HGF/c-Met/Snail/EMT pathway and combination of crizotinib reversed regorafenib tolerance.This study revealed the mechanism of HCC resistance to regorafenib and provided theoretical evidence for the combination of targeted therapy for late stage HCC.