Investigation Of The Role Of Aurora Kinase A And B Co-expression In Regulating The Proliferation Of Hepatocellular Carcinoma

?Aims? Hepatocellular carcinoma(HCC)is one of the deadliest malignant cancer in the world,with the largest number of HCC China accounts for 45% of the HCC cases globally.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 HCC.The purpose of this study is to clarify the relationship and clinical significance of Aurora A and B co-expression in HCC.?Methods? First of all,the m RNA levels of Aurora kinases A and B were analyzed in HCC according to Oncomine database,then their protein expression levels were detected by Western Blot in a total of 24 cases of HCC tissues and the expressed relationship was analyzed.The above results were further confirmed by immunohistochemical staining in 141 HCC cases.Secondly,the relationship of Aurora A and B protein expression with HCC prognosis was analyzed,respectively.Also,the relationship between their co-expression and prognosis was analyzed in HCC.Finally,with the inhibitors of Aurora kinases,the effects and mechanism of targeted inhibition were studied in HCC according to flow cytometry analysis of cell cycle profile and apoptosis,cell proliferation assay,Western Blot,etc.?Results? 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)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.?Conclusions? 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.