Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity
Securin induces genetic instability in colorectal cancer by inhibiting double-stranded DNA repair activity
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DOI：
10.1093/carcin/bgl202
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发表时间：
2007-03-01
期刊：
影响因子：
4.7
通讯作者：
McCabe, C. J.
中科院分区：
文献类型：
--
作者：
Kim, D. S.;Franklyn, J. A.;McCabe, C. J.
遗传不稳定性（GI）是肿瘤发展的标志性特征。Securin，也称为垂体肿瘤转化基因（PTTG），是一种有丝分裂检查点蛋白，在许多癌症中高度表达，与肿瘤侵袭性相关，并诱导甲状腺细胞中的GI。我们使用荧光间简单重复序列PCR评估GI主要由DNA断裂事件在19个结直肠肿瘤。GI值范围显著，Dukes'C&D期结直肠肿瘤比Dukes' A&B期肿瘤表现出更大的GI和更高的securin表达。与这些发现一致，我们观察到HCT 116细胞中GI响应securin过表达的剂量依赖性增加，以及在非转化的人成纤维细胞中。由于securin与裂殖酵母中一种新的DNA修复途径有关，我们使用宿主细胞再活化试验研究了其在哺乳动物细胞中化学毒性DNA损伤反应途径中的潜在作用。在HCT 116细胞中，Securin过表达抑制足叶乙甙诱导的双链DNA损伤修复活性，并抑制Ku异源二聚体功能。此外，我们观察到，securin和Ku70表现出相互的胞质核转位反应依托泊苷诱导的dsDNA损伤。我们的数据表明，通过抑制Ku70活性和抑制非同源末端连接dsDNA修复途径，securin可能是结肠直肠癌GI发展的关键基因。
Genetic instability (GI) is a hallmark feature of tumor development. Securin, also known as pituitary tumor transforming gene (PTTG), is a mitotic checkpoint protein which is highly expressed in numerous cancers, is associated with tumor invasiveness, and induces GI in thyroid cells. We used fluorescence inter-simple sequence repeat PCR to assess GI caused primarily by DNA breakage events in 19 colorectal tumors. GI values ranged significantly, with Dukes' stage C&D colorectal tumors exhibiting greater GI and higher securin expression than Dukes' stage A&B tumors. Consistent with these findings, we observed a dose-dependent increase in GI in HCT116 cells in response to securin overexpression, as well as in non-transformed human fibroblasts. As securin has been implicated in a novel DNA repair pathway in fission yeast, we investigated its potential role in chemotoxic DNA damage response pathways in mammalian cells, using host cell reactivation assays. Securin overexpression in HCT116 cells inhibited etoposide-induced double-stranded DNA damage repair activity, and repressed Ku heterodimer function. Additionally, we observed that securin and Ku70 showed a reciprocal cytosol-nuclear translocation in response to etoposide-induced dsDNA damage. Our data suggest that, by repressing Ku70 activity and inhibiting the non-homologous end-joining dsDNA repair pathway, securin may be a critical gene in the development of GI in colorectal cancer.