Jin Shunqian, Wang Xiaoxia, Tong Tong, Zhang Dongdong, Shi Ji, Chen Jie, Zhan Qimin
State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.17 Panjiayuan South Road, Chaoyang District, Beijing 10021, PR China; Department of Radiation Oncology, University of Pittsburgh School of Medicine, Cancer Institute, Pittsburgh, PA 15213, USA.
State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.17 Panjiayuan South Road, Chaoyang District, Beijing 10021, PR China; Department of Biochemistry and Molecular Biology, Shanxi Medical University, No. 56 South Road of Xinjian, Taiyuan 030001, PR China.
Mol Oncol. 2015 Jan;9(1):249-59. doi: 10.1016/j.molonc.2014.08.002. Epub 2014 Aug 27.
The Aurora-A gene encodes a serine/threonine protein kinase that is frequently overexpressed in several types of human tumors. The overexpression of Aurora-A has been observed to associate with the grades of differentiation, invasive capability and distant lymph node metastasis of esophageal squamous cell carcinoma (ESCC). However, the molecular mechanism by which Aurora-A promotes malignant development of ESCC is still largely unknown. In this study, we show that Aurora-A overexpression enhances tumor cell invasion and metastatic potential in vitro and in vivo. Furthermore, Aurora-A overexpression inhibits the degradation of β-catenin, promotes its dissociation from cell-cell contacts and increases its nuclear translocation. We also demonstrate for the first time that Aurora-A directly interacts with β-catenin and phosphorylates β-catenin at Ser552 and Ser675. Substitutions of serine residue with alanine at single or both positions substantially attenuate Aurora-A-mediated stabilization of β-catenin, abolish its cytosolic and nuclear localization as well as transcriptional activity. In addition, Aurora-A overexpression is significantly correlated with increased cytoplasmic β-catenin expression in ESCC tissues. In view of our results, we propose that Aurora-A-mediated phosphorylation of β-catenin is a novel mechanism of malignancy development of tumor.
极光激酶A（Aurora-A）基因编码一种丝氨酸/苏氨酸蛋白激酶，该激酶在多种人类肿瘤中经常过度表达。已观察到极光激酶A的过度表达与食管鳞状细胞癌（ESCC）的分化程度、侵袭能力及远处淋巴结转移相关。然而，极光激酶A促进ESCC恶性发展的分子机制仍不清楚。在本研究中，我们发现极光激酶A的过度表达在体外和体内均增强了肿瘤细胞的侵袭和转移潜能。此外，极光激酶A的过度表达抑制了β-连环蛋白的降解，促进其从细胞间接触中解离，并增加其核转位。我们还首次证明极光激酶A直接与β-连环蛋白相互作用，并在Ser552和Ser675位点磷酸化β-连环蛋白。在单个或两个位点将丝氨酸残基替换为丙氨酸可显著减弱极光激酶A介导的β-连环蛋白的稳定作用，消除其胞质和核定位以及转录活性。此外，在ESCC组织中，极光激酶A的过度表达与细胞质β-连环蛋白表达增加显著相关。基于我们的研究结果，我们提出极光激酶A介导的β-连环蛋白磷酸化是肿瘤恶性发展的一种新机制。
