Sugiura K, et al. - Experts examined the mechanism underlying yes-associated protein (YAP)-mediated cancer progression by focusing on the property of cancer stem cells (CSCs) in intrahepatic cholangiocarcinoma (ICC, second most frequent primary liver cancer after hepatocellular carcinoma and originates from the epithelium of the intrahepatic bile duct) which is immune to most chemotherapeutic agents. The positive YAP expression in 37 of 52 resected ICC subjects was shown by immunohistochemistry results. Poor prognosis in Kaplan-Meier analysis was exhibited by those with positive YAP expression. YAP expression was correlated with vimentin and the putative CSC marker, OV-6. In ICC cells, knockdown of YAP expression using specific siRNAs diminished OCT4 (stemness marker) expression in Western blot analyses and OV-6 and CD133 expression in flow cytometry analysis. In Western blot analyses, verteporfin (a YAP inhibitor) reduced N-cadherin (mesenchymal marker) and OCT4 expression. The impairment in CSC property and anoikis resistance in response to the reduction in YAP expression was shown by in vitro sphere formation and anoikis resistance assays. In ICC cells, verteporfin treatment stimulated the protein kinase B/mechanistic target of rapamycin signaling pathway and drastically impaired IL-6–stimulated STAT3 phosphorylation. Cell proliferation and tumor growth was inhibited by the combination of verteporfin and rapamycin, an inhibitor of the mechanistic target of rapamycin phosphorylation. Hence, it was concluded that verteporfin controlled multiple signaling pathways and, in combination with rapamycin, might be a hopeful therapeutic strategy for ICC treatment.