Hypoxia Signaling Regulates The Occurrence And Development Of Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)is one of the most common cancer types worldwide.Most HCC patients are diagnosed at advanced stages,and therefore there is an urgent need for new systemic therapies.Although sorafenib,a multikinase inhibitor with antiangiogenic and antiproliferative effects,currently sets the new standard for advanced HCC,tumor response rates are usually quite low.An understanding of the underlying mechanisms for sorafenib resistance is critical if outcomes are to be improved.In this study we tested the hypothesis that hypoxia caused by the antiangiogenic effects of sustained sorafenib therapy could induce sorafenib resistance as a cytoprotective adaptive response,thereby limiting sorafenib efficiency.We found that hypoxia protected HCC cells against sorafenib and hypoxia-inducible factor 2(HIF-2?)was required for the process.HPPCn,a novel growth factor,could stimulate cell growth and metastasis in hepatocellular carcinoma.HPPCn knockdown overcome sorafenib resistance through inhibiting HIF-2? by sequestering it in cytoplasm and promoting degradation by way of up-regulating Von Hippel-Lindau tumor suppressor(VHL).The combination ofHPPCn siRNA and sorafenib showed synergistically effects against metastasis both in vivo and in vitro.Synergistic tumor growth inhibition effects were also observed in subcutaneous and orthotopic hepatic tumors.Conclusion: Hypoxia induced by sustained sorafenib treatment confers sorafenib resistance to HCC through HIF-2? activation.Knockdown of HPPCn overcomes sorafenib resistance through VHL-dependent HIF-2? degradation.HPPCn siRNA in combination with sorafenib represents a promising strategy for HCC.