YAP is a critical oncogene in human cholangiocarcinoma

// Tiemin Pei 1,* , Yuejin Li 1,* , Jiabei Wang 1,* , Huanlai Wang 1,2,* , Yingjian Liang 1 , Huawen Shi 1 , Boshi Sun 1 , Dalong Yin 1 , Jing Sun 1 , Ruipeng Song 1 , Shangha Pan 1 , Yu Sun 1 , Hongchi Jiang 1 , Tongsen Zheng 1 and Lianxin Liu 1 1 Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 2 Department of General Surgery, Qiqihaer City Hospital of Traditional Chinese Medicine, Qiqihaer, China * These authors have contributed equally to this work Correspondence to: Lianxin Liu, email: // Tongsen Zheng, email: // Keywords : cholangiocarcinoma, YAP, gankyrin, AKT, tumorigenesis Received : January 13, 2015 Accepted : April 30, 2015 Published : May 08, 2015 Abstract Yes-associated protein (YAP), a transcriptional co-activator, has important regulatory roles in cell signaling and is dysregulated in a number of cancers. However, the role of YAP in cholangiocarcinoma (CCA) progression remains unclear. Here, we demonstrated that YAP was overexpressed in CCA cells and human specimens. High levels of nuclear YAP (nYAP) correlated with histological differentiation, TNM stage, metastasis and poor prognosis in CCA. Silencing YAP increased tumor sensitivity to chemotherapy and inhibited CCA tumorigenesis and metastasis both in vivo and in vitro . YAP overexpression in vivo and in vitro promoted CCA tumorigenesis and metastasis. Additionally, we found that YAP induced epithelial-mesenchymal transition (EMT) and formed a regulatory circuit with miR-29c, IGF1, AKT and gankyrin to promote the progression of CCA. Results of CCA tissue microarray showed positive correlations between nYAP and gankyrin or p-AKT expression. Combination of nYAP and gankyrin or p-AKT exhibited improved prognostic accuracy for CCA patients. In conclusion, YAP promotes carcinogenesis and metastasis by up-regulating gankyrin through activation of the AKT pathway.