Targeting hypoxia-inducible factor-2α enhances sorafenib antitumor activity via β-catenin/C-Myc-dependent pathways in hepatocellular carcinoma

Sorafenib is a type of multikinase inhibitor that exhibits antiangiogenic and antiproliferative effects; in addition, sorafenib is a unique first-line drug recommended for the treatment of advanced hepatocellular carcinoma (HCC). However, the effectiveness of HCC treatment remains poor due to acquired drug resistance. It has been suggested that hypoxia, induced as a results of the antiangiogenic effects of sustained sorafenib treatment, may be an important l'actor in somfenib resistance. The transcription factor hypoxiaHinducible factor (HIE)-2u has been reported to be associated with cell proliferation under hypoxic conditions; therefore, it was hypothesized that hypoxia may enhance tumor cell proliferation via this mechanism. The present study aimed to evaluate whether the knock-down of HIE-11 was able to enhance the therapeutic efficacy of sorafenib in order to effectively treat HCC. The results demonstrated that hypoxia protected HCC cells against somfenib; however, short hairpin RNA-HIE-2a transfection in combination with sorafcnib treatment exhibited a significantly synergistic effect against HCC cell proliferation. In addition, MCC cells acquired increased ii-catenin/C-Myc expression, which enhanced proliferation under hypoxic conditions; however, targeted knock-down of HIE-2u or C-Myc markedly decreased cell proliferation in HCC cells. In conclusion, the results of the present study indicated that the targeted knock-down of HIE-2u in combination with sorafenib may be a promising strategy for the treatment of HCC.