Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma
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Fuchen Liu1,2,*, Guangyong Wang3,*, Xiaoqiang Wang4,*, Zhihui Che2, Wei Dong1, Xinggang Guo1, Zhenguang Wang1, Ping Chen2, Daisen Hou2, Qi Zhang2, Wenli Zhang2, Yida Pan2, Dongqin Yang2, Hui Liu1
1The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
2Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai 200032, China
3Department of Gastroenterology, 411 Hospital of PLA, Shanghai 200081, China
4Department of Neurosurgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
*These authors contributed equally to this work
Dongqin Yang, email: firstname.lastname@example.org
Hui Liu, email: email@example.com
Keywords: Aurora A/B kinases, SNS-314, HCC, YAP, P21
Received: November 18, 2016 Accepted: February 20, 2017 Published: March 02, 2017
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 < 0.0001) and their co-overexpression (Aurora AHBH), associated with the worst prognosis, was an independent predictor for the survival. Importantly, with the lower IC50 and stronger anti-tumor effect than selective inhibitors, SNS-314, the pan-inhibitor of Aurora kinases, which induced YAP (Yes-associated protein) reduction and resulted in P21 accumulation, significantly promoted the polyploidy (> 4N) formation and apoptosis in HCC. High YAP expression (YAPH) was associated with Aurora AHBH, 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 AHBH 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.
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