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Yang G , Chang B , Yang F , Guo XQ , Cai KQ , Xiao X , Wang HM , Sen S , Hung MC , Mills GB , Chang S , Multani AS , Mercado-Uribe I , Liu JS
Aurora Kinase A Promotes Ovarian Tumorigenesis through Dysregulation of the Cell Cycle and Suppression of BRCA2
Clinical Cancer Research. 2010 Jun;16(12) :3171-3181
PMID: ISI:000278749400012    PMCID: PMC2930838   
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Abstract
Purpose: Aurora kinase A ( Aurora-A) is known to regulate genomic instability and tumorigenesis in multiple human cancers. The underlying mechanism, however, is not fully understood. We examined the molecular mechanism of Aurora-A regulation in human ovarian cancer. Experimental Design: Retrovirus-mediated small hairpin RNA ( shRNA) was used to silence the expression of Aurora-A in the ovarian cancer cell lines SKOV3, OVCA432, and OVCA433. Immunofluorescence, Western blotting, flow cytometry, cytogenetic analysis, and animal assay were used to test centrosome amplification, cell cycle alteration, apoptosis, DNA damage response, tumor growth, and genomic instability. Immunostaining of BRCA2 and Aurora-A was done in ovarian, pancreatic, breast, and colon cancer samples. Results: Knockdown of Aurora-A reduced centrosome amplification, malformation of mitotic spindles, and chromosome aberration, leading to decreased tumor growth. Silencing Aurora-A attenuated cell cycle progression and enhanced apoptosis and DNA damage response by restoring p21, pRb, and BRCA2 expression. Aurora-A was inversely correlated with BRCA2 in high-grade ovarian serous carcinoma, breast cancer, and pancreatic cancer. In high-grade ovarian serous carcinoma, positive expression of BRCA2 predicted increased overall and disease-free survival, whereas positive expression of Aurora-A predicted poor overall and disease-free survival ( P < 0.05). Moreover, an increased Aurora-A to BRCA2 expression ratio predicted poor overall survival ( P = 0.047) compared with a decreased Aurora-A to BRCA2 expression ratio. Conclusion: Aurora-A regulates genomic instability and tumorigenesis through cell cycle dysregulation and BRCA2 suppression. The negative correlation between Aurora-A and BRCA2 exists in multiple cancers, whereas the expression ratio of Aurora-A to BRCA2 predicts ovarian cancer patient outcome. Clin Cancer Res; 16( 12); 3171-81. (C)2010 AACR.
Notes
Yang, Gong Chang, Bin Yang, Fan Guo, Xiaoqing Cai, Kathy Qi Xiao, Xue (Sherry) Wang, Huamin Sen, Subrata Hung, Mien-Chie Mills, Gordon B. Chang, Sandy Multani, Asha S. Mercado-Uribe, Imelda Liu, Jinsong National Institutes of Health [R01CA131183-01A2, IP50CA83638, 5P50CA116199-05]; institutional research grant ( IRG) ; National Cancer Institute [CA016672] J. Liu is supported by an R01 grant from the National Institutes of Health ( R01CA131183-01A2) and by Specialized Programs of Research Excellence ( SPORE) grant in ovarian cancer ( IP50CA83638) and breast cancer ( 5P50CA116199-05), and also institutional research grant ( IRG). This work was also supported in part by Cancer Center Core grant CA016672 from the National Cancer Institute. F. Yang was a visiting scientist from the Department of Gynecologic Pathology, West China Second University Hospital, Sichuan University, Sichuan, China; X. Xiao was a visiting graduate student from the Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Sichuan, China; B. Chang was a visiting scientist and X. Guo a visiting professor from the Departments of Pathology and Gynecology, respectively, Shihezi University, Xingjiang, China. 50 Amer assoc cancer research; 615 chestnut st, 17th floor, philadelphia, pa 19106-4404 usa 610qn