Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma

// Fuchen Liu 1, 2, * , Guangyong Wang 3, * , Xiaoqiang Wang 4, * , Zhihui Che 2 , Wei Dong 1 , Xinggang Guo 1 , Zhenguang Wang 1 , Ping Chen 2 , Daisen Hou 2 , Qi Zhang 2 , Wenli Zhang 2 , Yida Pan 2 , Dongqin Yang 2 , Hui Liu 1 1 The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China 2 Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200032, China 3 Department of Gastroenterology, 411 Hospital of PLA, Shanghai 200081, China 4 Department of Neurosurgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China * These authors contributed equally to this work Correspondence to: Dongqin Yang, email: kobesakura@163.com Hui Liu, email: liuhuigg@hotmail.com Keywords: Aurora A/B kinases, SNS-314, HCC, YAP, P21 Received: November 18, 2016 Accepted: February 20, 2017 Published: March 02, 2017 ABSTRACT The Aurora kinases A and B control tumorigenesis by inhibiting apoptosis and promoting proliferation and metastasis, however, it remains unknown whether Aurora A and B overexpressed concomitantly and its clinical significance in hepatocellular carcinoma (HCC). Here, we obsearved Aurora A and B tended to overexpress parallelly on protein level ( r = 0.8679, P 4N) formation and apoptosis in HCC. High YAP expression (YAP H ) was associated with Aurora A H B H , and appeared to be an independent predictor for survival, but P21 not. Moreover, silencing YAP also induced P21 accumulation, and knockdown P21, which enhanced YAP accumulation and weakened the SNS-314-induced YAP reduction, impaired SNS-314-induced apoptosis. Therefore, P21 enhanced the apoptotic effect of SNS-314 in HCC. Taken together, our findings indicated Aurora kinases/YAP/P21 was an oncogenic signaling axis in HCC, and revealed targeting Aurora A H B H induced apoptosis by YAP suppression. Our results also provided a solid evidence for SNS-314 as a potential targeted therapy, and a proof-of-concept evidence for a possible combined therapy of SNS-314 plus Hippo pathway inhibitors on HCC.