YAP promotes sorafenib resistance in hepatocellular carcinoma by upregulating survivin

Abstract Background Sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), but its use is hampered by the secondary drug resistance. Yes-associated protein (YAP) is the crucial downstream effector of the Hippo signaling pathway, which is crucial for liver tumorigenesis. However, the underlying mechanism regarding YAP and sorafenib resistance remains unclear. Methods Western blotting, flow cytometry, and CCK-8 assay were used to confirm the role of YAP in HCC sorafenib resistance. RT-PCR and western blotting were then performed to identify survivin as downstream of YAP, whereas rescue experiments were performed to confirm that YAP induces sorafenib resistance via survivin. Further, western blotting, flow cytometry, and an in vivo xenograft model were used to evaluate the function of verteporfin in combination with sorafenib in HCC. Results We found that sorafenib enhances YAP nuclear accumulation and activates YAP, which promotes sorafenib resistance by inhibiting apoptosis in HCC cells. Moreover, survivin acted as a downstream mediator of YAP to resist sorafenib-induced apoptosis. Pharmacological inhibition of YAP by verteporfin inhibited HCC cells proliferation and restored the sensitivity to sorafenib. Moreover, verteporfin in combination with sorafenib significantly suppressed HepG2 xenograft tumor growth. Conclusions Our study indicates that YAP promotes sorafenib resistance in HCC through upregulating survivin expression. Targeting YAP may be a potential therapeutic strategy to improve the antitumor effects of sorafenib in HCC.