Aurora kinase A promotes ovarian tumorigenesis through dysregulation of the cell cycle and suppression of BRCA2.
Aurora kinase A promotes ovarian tumorigenesis through dysregulation of the cell cycle and suppression of BRCA2.
复制标题
DOI：
10.1158/1078-0432.ccr-09-3171
复制
发表时间：
2010-06-15
期刊：
影响因子：
--
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Yang G;Chang B;Yang F;Guo X;Cai KQ;Xiao XS;Wang H;Sen S;Hung MC;Mills GB;Chang S;Multani AS;Mercado-Uribe I;Liu J
已知极光激酶A（Aurora-A）调节多种人类癌症中的基因组不稳定性和肿瘤发生。然而，其基本机制尚未完全了解。我们研究了人类卵巢癌中Aurora-A调控的分子机制。逆转录病毒介导的小发夹RNA（shRNA）用于沉默卵巢癌细胞系SKOV 3、OVCA 432和OVCA 433中Aurora-A的表达。采用免疫荧光、Western印迹、流式细胞术、细胞遗传学分析和动物试验检测中心体扩增、细胞周期改变、细胞凋亡、DNA损伤反应、肿瘤生长和基因组不稳定性。BRCA 2和Aurora-A的免疫染色在卵巢癌、胰腺癌、乳腺癌和结肠癌样本中进行。Aurora-A的敲除减少了中心体扩增、有丝分裂纺锤体畸形和染色体畸变，导致肿瘤生长减少。沉默Aurora-A通过恢复p21、pRb和BRCA 2表达减弱细胞周期进程并增强凋亡和DNA损伤反应。Aurora-A与BRCA 2在高级别卵巢浆液性癌、乳腺癌和胰腺癌中呈负相关。在高级别卵巢浆液性癌中，BRCA 2阳性表达预测总生存期和无病生存期增加，而Aurora-A阳性表达预测总生存期和无病生存期较差（P < 0.05）。此外，Aurora-A与BRCA 2表达比率增加与Aurora-A与BRCA 2表达比率降低相比，预测总生存率较差（P = 0.047）。Aurora-A通过细胞周期失调和BRCA 2抑制调节基因组不稳定性和肿瘤发生。Aurora-A和BRCA 2之间的负相关性存在于多种癌症中，而Aurora-A与BRCA 2的表达比率可预测卵巢癌患者的预后。
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. 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. 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. 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.