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Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma
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 tende...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438621/ https://www.ncbi.nlm.nih.gov/pubmed/28427193 http://dx.doi.org/10.18632/oncotarget.15853 |
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author | Liu, Fuchen Wang, Guangyong Wang, Xiaoqiang Che, Zhihui Dong, Wei Guo, Xinggang Wang, Zhenguang Chen, Ping Hou, Daisen Zhang, Qi Zhang, Wenli Pan, Yida Yang, Dongqin Liu, Hui |
author_facet | Liu, Fuchen Wang, Guangyong Wang, Xiaoqiang Che, Zhihui Dong, Wei Guo, Xinggang Wang, Zhenguang Chen, Ping Hou, Daisen Zhang, Qi Zhang, Wenli Pan, Yida Yang, Dongqin Liu, Hui |
author_sort | Liu, Fuchen |
collection | PubMed |
description | 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 A(H)B(H)), 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 (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. |
format | Online Article Text |
id | pubmed-5438621 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-54386212017-05-24 Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma Liu, Fuchen Wang, Guangyong Wang, Xiaoqiang Che, Zhihui Dong, Wei Guo, Xinggang Wang, Zhenguang Chen, Ping Hou, Daisen Zhang, Qi Zhang, Wenli Pan, Yida Yang, Dongqin Liu, Hui Oncotarget Research Paper 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 A(H)B(H)), 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 (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. Impact Journals LLC 2017-03-02 /pmc/articles/PMC5438621/ /pubmed/28427193 http://dx.doi.org/10.18632/oncotarget.15853 Text en Copyright: © 2017 Liu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Liu, Fuchen Wang, Guangyong Wang, Xiaoqiang Che, Zhihui Dong, Wei Guo, Xinggang Wang, Zhenguang Chen, Ping Hou, Daisen Zhang, Qi Zhang, Wenli Pan, Yida Yang, Dongqin Liu, Hui Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma |
title | Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma |
title_full | Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma |
title_fullStr | Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma |
title_full_unstemmed | Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma |
title_short | Targeting high Aurora kinases expression as an innovative therapy for hepatocellular carcinoma |
title_sort | targeting high aurora kinases expression as an innovative therapy for hepatocellular carcinoma |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438621/ https://www.ncbi.nlm.nih.gov/pubmed/28427193 http://dx.doi.org/10.18632/oncotarget.15853 |
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