MESSENGER-RNA LEVELS OF XPAC AND ERCC1 IN OVARIAN-CANCER TISSUE CORRELATE WITH RESPONSE TO PLATINUM-BASED CHEMOTHERAPY
MESSENGER-RNA LEVELS OF XPAC AND ERCC1 IN OVARIAN-CANCER TISSUE CORRELATE WITH RESPONSE TO PLATINUM-BASED CHEMOTHERAPY
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DOI：
10.1172/jci117388
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发表时间：
1994-08-01
影响因子：
15.9
通讯作者：
REED, E
中科院分区：
文献类型：
--
作者：
DABHOLKAR, M;VIONNET, J;REED, E
核苷酸切除修复是一种在自然界中高度保守的DNA修复途径，在大肠杆菌、酵母和哺乳动物细胞中也有类似的修复系统。限速步骤，DNA损伤识别和切除，是由基因ERCC1和XPAC的蛋白产物决定的。因此，我们评估了28例恶性卵巢癌患者的ERCC1和XPAC mRNA水平，这些患者是在给予铂基化疗之前采集的。与临床对治疗敏感的患者（n = 15）相比，临床对治疗耐药的患者（n = 13）的肿瘤组织中ERCC1 mRNA总水平（P = 0.059）、ERCC1 mRNA全长转录本（P = 0.026）和XPAC mRNA （P = 0.011）水平更高。在其中的19个组织中，评估了ERCC1 mRNA选择性剪接的百分比。ERCC1剪接是高度可变的，在应答者和无应答者之间没有观察到差异。在应答者中，选择性剪接的物种占总ERCC1 mRNA的2-58%（中位数= 18%），在无应答者中占4-71%（中位数= 13%）。这些数据表明，DNA切除修复基因ERCC1和XPAC在临床铂类化合物耐药的卵巢癌患者组织中具有更高的活性。这些数据还表明，体内卵巢癌组织中ERCC1 mRNA剪接高度可变，无论这些组织是否对铂类药物治疗敏感。
Nucleotide excision repair is a DNA repair pathway that is highly conserved in nature, with analogous repair systems described in Escherichia coli, yeast, and mammalian cells. The rate-limiting step, DNA damage recognition and excision, is effected by the protein products of the genes ERCC1 and XPAC. We therefore assessed mRNA levels of ERCC1 and XPAC in malignant ovarian cancer tissues from 28 patients that were harvested before the administration of platinum-based chemotherapy. Cancer tissues from patients whose tumors were clinically resistant to therapy (n = 13) showed greater levels of total ERCC1 mRNA (P = 0.059), full length transcript of ERCC1 mRNA (P = 0.026), and XPAC mRNA (P = 0.011), as compared with tumor tissues from those individuals clinically sensitive to therapy (n = 15). In 19 of these tissues, the percentage of alternative splicing of ERCC1 mRNA was assessed. ERCC1 splicing was highly variable, with no difference observed between responders and nonresponders. The alternatively spliced species constituted 2-58% of the total ERCC1 mRNA in responders (median = 18%) and 4-71% in nonresponders (median = 13%). These data suggest greater activity of the DNA excision repair genes ERCC1 and XPAC in ovarian cancer tissues of patients clinically resistant to platinum compounds. These data also indicate highly variable splicing of ERCC1 mRNA in ovarian cancer tissues in vivo, whether or not such tissues are sensitive to platinum-based therapy.