Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas - Synergistic effect with mutant p53 on tumor growth and chromosomal instability - Evidence of E2F-1 transcriptional control over hCdt1
Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas - Synergistic effect with mutant p53 on tumor growth and chromosomal instability - Evidence of E2F-1 transcriptional control over hCdt1
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DOI：
10.1016/s0002-9440(10)63393-7
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发表时间：
2004-10-01
影响因子：
6
通讯作者：
Gorgoulis, VG
中科院分区：
文献类型：
--
作者：
Karakaidos, P;Taraviras, S;Gorgoulis, VG
复制许可确保每个细胞周期复制一次，这对基因组稳定性至关重要。两个关键的许可因子Cdc 6和Cdt 1的过表达导致低等真核生物和最近人类细胞系中的过度复制和染色体不稳定性（CIN）。在这份报告中，我们分析了一系列非小细胞肺癌中hCdt 1、hCdc 6和hGeminin（hCdt 1抑制剂）的表达，并研究了它们与G（1）/S期调节因子、肿瘤动力学和倍性之间的关系。这是第一次研究这些基本的许可要素在原发性人类肺癌。我们在此证明hCdt 1和hCdc 6水平升高（超过4倍）分别在43%和50%的肿瘤，而异常表达hGeminin观察到49%的情况下（低表达，12%;过表达，37%）。hCdt 1表达与hCdc 6和E2 F-1水平呈正相关（分别为P = 0.001和P = 0.048）。支持E2 F-1和hCdt 1之间观察到的联系，我们提供的证据表明，E2 F-1上调培养的哺乳动物细胞中的hCdt 1启动子。有趣的是，hGeminin过表达与hCdt 1水平增加有统计学相关性（P = 0.025）。关于hCdt 1和/或hCdc 6过表达肿瘤的动力学和倍性状态，与携带完整p53的肿瘤相比，p53突变病例显示出显著增加的肿瘤生长值（生长指数; GI）和非整倍性/CIN（GI P = 0.008，CIN P = 0.001）。这些结果的意义是强调的事实，后者的参数是独立的p53在hCdt 1-hCdc 6正常表达的情况下。累积起来，上述结果表明hCdt 1-hCdc 6过表达和muplant-P53对非小细胞中肿瘤生长和CIN的协同作用。肺癌
Replication licensing ensures once per cell cycle replication and is essential for genome stability. Overexpression of two key licensing factors, Cdc6 and Cdt1, leads to overreplication and chromosomal instability (CIN) in lower eukaryotes and recently in human cell lines. In this report, we analyzed hCdt1, hCdc6, and hGeminin, the hCdt1 inhibitor expression, in a series of non-small-cell lung carcinomas, and investigated for putative relations with G(1)/S phase regulators, tumor kinetics, and ploidy. This is the first study of these fundamental licensing elements in primary human lung carcinomas. We herein demonstrate elevated levels (more than fourfold) of hCdt1 and hCdc6 in 43% and 50% of neoplasms, respectively, whereas aberrant expression of hGeminin was observed in 49% of cases (underexpression, 12%; overexpression, 37%). hCdt1 expression positively correlated with hCdc6 and E2F-1 levels (P = 0.001 and P = 0.048, respectively). Supportive of the observed link between E2F-1 and hCdt1, we provide evidence that E2F-1 up-regulates the hCdt1 promoter in cultured mammalian cells. Interestingly, hGeminin overexpression was statistically related to increased hCdt1 levels (P = 0.025). Regarding the kinetic and ploidy status of hCdt1- and/or hCdc6-overexpressing tumors, p53-mutant cases exhibited significantly increased tumor growth values (Growth index; GI) and aneuploidy/CIN compared to those bearing intact p53 (P = 0.008 for GI, P = 0.001 for CIN). The significance of these results was underscored by the fact that the latter parameters were independent of p53 within the hCdt1-hCdc6 normally expressing cases. Cumulatively, the above suggest a synergistic effect between hCdt1-hCdc6 overexpression and mutant-P53 over tumor growth and CIN in non-small-cell. lung carcinomas.