Evaluation of YAP as a therapeutic target in HCC and CCA

Abstract

BackgroundFor Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the outcome is dismal; incidence is rapidly increasing, and mechanistic understanding is limited. YAP, the effector of Hippo signaling pathway, is an oncoprotein that promotes cell proliferation and inhibits apoptosis. Genetic manipulation of YAP results in biliary hamartoma and HCC. Therefore, we hypothesize that YAP is driver of liver cancer and a potential therapeutic target.
MethodsExpression of YAP and its transcriptional targets GPC3 and Survivin was surveyed in normal human liver and primary liver cancer tissues. Efficacy of YAP inhibitor Vertepofin and Survivin inhibitor YM155 was tested in HCC and CCA cell lines with MTT assay.ResultsCompared to the non‐tumor tissue, nuclear YAP expression significantly increased in both HCC and ICC specimens. Nuclear YAP levels significantly correlate with nuclear Survivin levels in HCC and ICC tissues, but not with GPC3 in HCC tissues. We also found that verteporfin and YM155 suppressed HCC and CCA cell proliferation in vitro and had an additive effect to sorafenib treatment. Moreover, HCC cell lines with higher YAP expression were more sensitive to verteporfin treatment.ConclusionsOur findings suggested that YAP contributes to primary liver tumorigenesis and likely mediates its oncogenic effects through modulating Survivin expression. Small molecules that target YAP and Survivin activity could be a promising therapeutic strategy for treatment of HCC and CCA with high YAP expression.