Regorafenib reverses HGF-induced sorafenib resistance by inhibiting epithelial-mesenchymal transition in hepatocellular carcinoma.

Sorafenib resistance is one of the major obstacles towards achieving a better outcome in patients with advanced hepatocellular carcinoma (HCC), in which aberrant activation of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition pathway is frequently observed. Here, we report that HCC cells develop sorafenib resistance following HGF stimulation. Furthermore, HGF activates the downstream extracellular signal-related kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) pathway and induces epithelial-mesenchymal transition (EMT) by up-regulating Snail in HCC cells. Inhibition of ERK and STAT3 abolished the rescue effect of HGF by down-regulating Snail and EMT. Moreover, phosphoinositide 3-kinase/Akt was also activated in HGF-treated HCC cells, although it had no effect on Snail expression. Notably, we also found that regorafenib reversed HGF-induced sorafenib resistance by inhibiting ERK and STAT3, and subsequently down-regulating Snail and EMT. Taken together, our results indicate that HGF induces sorafenib resistance by activating phosporylated (P)-ERK/Snail/EMT and P-STAT3/Snail/EMT pathways. Inhibition of P-ERK and P-STAT3 by regorafenib can block HGF-induced EMT, thereby reversing HGF-induced sorafenib resistance.