Departments of Molecular & Genetic Toxicology, Cancer Center of Nanjing Medical University, Nanjing, China.
Oncogene. 2010 Apr 1;29(13):1920-8. doi: 10.1038/onc.2009.484. Epub 2010 Jan 11.
Xeroderma pigmentosum group F (XPF) has an essential role in the nucleotide excision repair pathway that removes a wide variety of DNA lesions. We hypothesized that genetic variants in XPF are associated with bladder cancer risk and recurrence. We selected three tagging single nucleotide polymorphisms (tagSNPs) from the HapMap database for the Chinese and genotyped them in a two-stage case-control study to evaluate the association and further examined the functionality of a novel polymorphism in the promoter. The two-stage analysis found that the rs744154 tagSNP in the XPF intron 1, which was linkage disequilibrium with the -357A>C polymorphism in the promoter region, was associated with a protective effect on bladder cancer risk. Electrophoretic mobility shift assay (EMSA) further revealed that the -357C allele decreased the binding ability of transcriptional factors to the XPF promoter. The vector construct containing the -357C allele had a lower luciferase expression than did the -357A allele. The -357C allele in the transcription factor-binding site was also associated with decreased expression levels of both XPF mRNA and protein in bladder cancer tissues. Furthermore, patients with the -357C allele had a shorter overall recurrence-free survival than did patients with the -357A allele. Our results suggest that the XPF promoter -357A>C polymorphism may regulate the expression of XPF and thereby contribute to susceptibility to and prognosis of bladder cancer. Further larger studies with different populations are warranted to confirm these findings.
着色性干皮病组 F（XPF）在核苷酸切除修复途径中具有重要作用，该途径可去除多种 DNA 损伤。我们假设 XPF 中的遗传变异与膀胱癌风险和复发有关。我们从 HapMap 数据库中选择了三个标签单核苷酸多态性（tagSNP）用于中国人群，并在两阶段病例对照研究中对其进行了基因分型，以评估关联，并进一步研究了启动子中新发现的多态性的功能。两阶段分析发现，XPF 内含子 1 中的 rs744154 tagSNP 与启动子区域的-357A>C 多态性呈连锁不平衡，与膀胱癌风险的保护作用相关。电泳迁移率变动分析（EMSA）进一步表明，-357C 等位基因降低了转录因子与 XPF 启动子的结合能力。含有-357C 等位基因的载体构建体的荧光素酶表达低于-357A 等位基因。转录因子结合位点中的-357C 等位基因也与膀胱癌组织中 XPF mRNA 和蛋白质的表达水平降低相关。此外，携带-357C 等位基因的患者的总无复发生存率低于携带-357A 等位基因的患者。我们的结果表明，XPF 启动子-357A>C 多态性可能调节 XPF 的表达，从而影响膀胱癌的易感性和预后。需要进行不同人群的更大规模研究来证实这些发现。
