BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 During Cisplatin Treatment in Ovarian Cancer Cells
BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 During Cisplatin Treatment in Ovarian Cancer Cells
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DOI：
10.1177/117727190600100007
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发表时间：
2006-01
影响因子：
3.8
通讯作者：
A. Horiuchi;Cuiju Wang;Norihiko Kikuchi;R. Osada;T. Nikaido;I. Konishi
中科院分区：
文献类型：
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作者：
A. Horiuchi;Cuiju Wang;Norihiko Kikuchi;R. Osada;T. Nikaido;I. Konishi
BRCA1是一种肿瘤抑制因子，在DNA双链断裂的修复中起着至关重要的作用，其异常与遗传性卵巢癌综合征有关。最近有报道称，BRCA1通过其启动子超甲基化而降低表达在散发性卵巢癌中也很常见，并且BRCA1表达阴性的卵巢癌患者预后良好。为了解决BRCA1表达是否在化疗反应中起作用，我们分析了BRCA1抑制对卵巢癌细胞对顺铂和紫杉醇敏感性的影响。将BRCA1基因特异性siRNA转染到3株不同p53状态的卵巢癌细胞系中。通过转染BRCA1- sirna降低BRCA1的表达导致p53-野生A2780细胞对顺铂的敏感性增加5.3倍，但在p53突变的A2780/CDDP和p53缺失的SKOV3细胞中没有。在紫杉醇敏感性方面，BRCA1抑制在3个细胞系中均未引起显著变化。对于电离辐射敏感性，BRCA1抑制在A2780细胞中也显示出显著更高的敏感性。生长曲线和细胞周期分析显示，brca1 - sirna转染的A2780细胞与对照细胞无显著差异。然而，抑制BRCA1的顺铂治疗显示A2780细胞中凋亡显著增加，p53和p21表达上调。因此，BRCA1表达降低通过上调p53和p21增强顺铂敏感性和细胞凋亡，但不影响紫杉醇敏感性。BRCA1的表达可能是卵巢癌顺铂耐药的重要生物标志物。
BRCA1 is a tumor suppressor which plays a crucial role in the repair of DNA double-strand breaks, and its abnormality is responsible for hereditary ovarian cancer syndrome. It has recently been reported that reduced expression of BRCA1 is also common in sporadic ovarian carcinoma via its promoter hypermethylation, and that ovarian carcinoma patients negative for BRCA1 expression showed favorable prognosis. To address if BRCA1 expression plays a role in the chemotherapeutic response, we analyzed the effect of BRCA1 suppression on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Specific siRNA for BRCA1 gene was transfected into 3 ovarian cancer cell lines with various p53 status. Reduced expression of BRCA1 by transfection of BRCA1-siRNA resulted in a 5.3-fold increase in sensitivity to cisplatin in p53-wild A2780 cells, but not in p53-mutated A2780/CDDP and p53-deleted SKOV3 cells. Regarding the sensitivity to paclitaxel, BRCA1 suppression caused no significant changes in all the 3 cell lines. For ionizing radiation sensitivity, BRCA1 suppression also showed a significant higher sensitivity in A2780 cells. Growth curve and cell cycle analyses showed no significant differences between BRCA1-siRNA-transfected A2780 cells and control cells. However, cisplatin treatment under suppression of BRCA1 showed a significantly increased apoptosis along with up-regulation of p53 and p21 in A2780 cells. Accordingly, reduced expression of BRCA1 enhances the cisplatin sensitivity and apoptosis via up-regulation of p53 and p21, but does not affect the paclitaxel sensitivity. Expression of BRCA1 might be an important biomarker for cisplatin resistance in ovarian carcinoma.