A novel functional polymorphism in the Cdc6 promoter is associated with the risk for hepatocellular carcinoma
A novel functional polymorphism in the Cdc6 promoter is associated with the risk for hepatocellular carcinoma
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DOI：
10.1016/j.mrfmmm.2008.06.006
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发表时间：
2008-08-25
影响因子：
2.3
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
--
作者：
Xiong, Xing-Dong;Fang, Jian-Hong;Zhuang, Shi-Mei
Cdc6 对于 DNA 复制至关重要，其失调与癌发生有关。迄今为止，Cdc6启动子多态性的生物学意义仍不清楚。在本研究中，我们旨在评估 Cdc6 -515A > G 多态性的影响。 (rs4134994) 对个体对癌症的易感性和 Cdc6 的功能的影响。在 387 名肝细胞癌 (HCC) 和 389 名年龄和性别匹配的健康受试者中对 Cdc6 -515A > G 多态性进行了基因分型。然后通过无条件逻辑回归分析并调整年龄、性别和 HBV 状态来估计基因型与 HCC 风险之间的关联。与 AA 纯合子相比，纯合 GG 基因型（调整后 OR = 0.36，95% 置信区间 (CI) = 0.18-0.72，P = 0.004）或组合 AG/GG 基因型（调整后 OR = 0.56，95% CI = 0.36-0.86，P= 0.008）与降低的风险显着相关。肝癌。此外，使用荧光素酶报告系统的分析表明，与A等位基因启动子相比，G等位基因Cdc6启动子的转录活性降低。这些结果表明，具有 G 等位基因的个体可能具有降低的 Cdc6 表达，因此患 HCC 的风险降低。使用电泳迁移率变动分析 (EMSA) 的进一步研究表明，G 等位基因与核蛋白具有更强的结合强度，可能作为 Cdc6 转录的负调节因子。我们的研究结果表明，-515A > G 多态性可能影响 Cdc6 启动子与核蛋白的结合亲和力，进而影响 Cdc6 的表达，从而调节个体对 HCC 的易感性。 (c) 2008 Elsevier B.V. 保留所有权利。
Cdc6 is essential for DNA replication and its deregulation is involved in carcinogenesis. To date, the biological significance of the polymorphism in Cdc6 promoter is still unknown. In this study, we aimed to evaluate the influence of the Cdc6 -515A > G polymorphism. (rs4134994) on the individual's susceptibility to cancer and on the function of Cdc6. The Cdc6 -515A > G polymorphism was genotyped in 387 hepatocellular carcinoma (HCC) and 389 age- and sex-matched healthy subjects. The association between the genotypes and the risk for HCC was then estimated by unconditional logistic regression analysis with adjustment for age, sex and HBV status. Compared with the AA homozygotes, the homozygous GG genotype (adjusted OR = 0.36,95% confidence interval (CI) = 0.18-0.72, P = 0.004) or the combined AG/GG genotypes (adjusted OR = 0.56, 95% CI = 0.36-0.86, P= 0.008) were statistically significantly associated with the reduced risk for HCC. Moreover, the analysis using luciferase reporter system showed that the G-allelic Cdc6 promoter displayed a decreased transcriptional activity compared with the A-allelic one. These results indicate that the individuals with G allele may have reduced Cdc6 expression and are therefore in reduced risk for HCC. Further investigation using electrophoretic mobility shift assay (EMSA) revealed that the G allele had a stronger binding strength to nuclear protein(s) which might function as negative regulator(s) for Cdc6 transcription. Our findings suggest that the -515A > G polymorphism may affect the Cdc6 promoter binding affinity with nuclear protein(s) and in turn the Cdc6 expression, which consequently modulates the individual's susceptibility to HCC. (c) 2008 Elsevier B.V. All rights reserved.