Clinicopathological and functional significance of XRCC1 expression in ovarian cancer
Clinicopathological and functional significance of XRCC1 expression in ovarian cancer
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DOI：
10.1002/ijc.27980
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发表时间：
2013-06-15
影响因子：
6.4
通讯作者：
Madhusudan, Srinivasan
中科院分区：
文献类型：
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作者：
Abdel-Fatah, Tarek;Sultana, Rebeka;Madhusudan, Srinivasan
X-射线修复交叉互补基因1(XRCC1)是DNA碱基切除修复、单链断裂修复和核苷酸切除修复所必需的。我们探讨了XRCC1在卵巢癌中的表达及其临床病理和功能意义。我们研究了195例卵巢癌组织中XRCC1蛋白的表达，并与临床病理变量和生存结果进行了相关性分析。在一组XRCC1缺陷和熟练的中国仓鼠和人类癌细胞中进行了顺铂化疗敏感性的功能临床前研究。细胞克隆形成试验、中性彗星试验、H_2AX免疫细胞化学和流式细胞仪分析。在卵巢癌中，48%的肿瘤XRCC1表达阳性，且与高分期(p=0.006)、浆液性肿瘤(p=0.008)、次优肿胀(p=0.004)和铂耐药(p<；0.0001)显著相关。XRCC1阳性患者的死亡风险(p=0.007)和进展风险(p<；0.0001)增加了一倍。在多变量COX模型中，XRCC1的表达与肿瘤特异性[p=0.038]和无进展生存率[p=0.003]独立相关。临床前，XRCC1阴性细胞对顺铂的敏感性高于XRCC1阳性细胞。XRCC1阴性细胞对顺铂的敏感性与DNA双链断裂和G2/M期细胞周期停滞有关。XRCC1的表达与患者不良的临床病理和生存结局有关。临床前数据为顺铂在XRCC1阴性细胞中的敏感性提供了机械功能证据。XRCC1是一种很有前途的卵巢癌预测生物标志物。
X-ray repair cross-complementing gene 1 (XRCC1) is essential for DNA base excision repair, single strand break repair and nucleotide excision repair. We investigated clinicopathological and functional significance of XRCC1 expression in ovarian cancers. XRCC1 protein expression was evaluated in 195 consecutive human ovarian cancers and correlated with clinicopathological variables and survival outcomes. Functional preclinical studies were conducted in a panel of XRCC1 deficient and proficient Chinese hamster and Human cancer cells for cisplatin chemosensitivity. Clonogenic assay, neutral COMET assay, H2AX immunocytochemistry and flow cytometric analyses were performed in cells. In ovarian cancer, 48% of the tumors were positive for XRCC1 expression and significantly associated with higher stage (p = 0.006), serous type tumors (p = 0.008), suboptimal de-bulking (p = 0.004) and platinum resistance (p < 0.0001). Positive XRCC1 had twofold increase of risk of death (p = 0.007) and progression (p < 0.0001). In the multivariate Cox model, XRCC1 expression was independently associated with cancer specific [p = 0.038] and progression free survival [p = 0.003]. Preclinically, XRCC1 negative cells were sensitive to cisplatin compared to XRCC1 positive cells. Sensitivity to cisplatin in XRCC1 negative cells was associated with accumulation of DNA double strand breaks and G2/M cell cycle arrest. XRCC1 expression is associated with adverse clinicopathological and survival outcomes in patients. Preclinical data provides mechanistic functional evidence for cisplatin sensitivity in XRCC1 negative cells. XRCC1 is a promising predictive biomarker in ovarian cancer.