Brain Tumor Program; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA ; Infectious Diseases and Microbiology; University of Pittsburgh Graduate School of Public Health; Pittsburgh, PA USA.
Oncoimmunology. 2012 Jul 1;1(4):487-492. doi: 10.4161/onci.19964.
We have previously reported that the single nucleotide polymorphism (SNP) rs12553612 in IFNA8 is associated with better overall survival of glioma patients with the AA-genotype compared with patients with the AC-genotype. As rs12553612 is located in the IFNA8 promoter, we hypothesized that the A-allele allows for an enhanced IFNA8 promoter activity compared with the C-allele. Reporter assays in the human monocyte derived THP-1 cell line demonstrated a superior promoter activity of the A-allele compared with the C-allele. Electrophoretic mobility shift assays (EMSA) further demonstrated that the A-genotype specifically binds to more nuclear proteins than the C-genotype, including the transcription factor Oct-1. Further, co-transfection of plasmids encoding Oct-1 and the reporter constructs revealed that Oct-1 enhanced the promoter activity with the A- but not the C-allele. Taken together, our data demonstrate that the A-allele in the rs12553612 SNP, which is associated with better glioma patient survival, allows for IFNA8 transcription by allowing for Oct-1 binding, which is absent in patients with C allele, and suggests a molecular mechanism of IFNA8 mediated immune-surveillance of glioma progression.
我们之前曾报道，IFNA8 基因上的单核苷酸多态性（SNP）rs12553612 与 AA 基因型的胶质母细胞瘤患者的总体生存率优于 AC 基因型患者相关。由于 rs12553612 位于 IFNA8 启动子区域，我们假设 A 等位基因与 C 等位基因相比，能够增强 IFNA8 启动子的活性。在人单核细胞衍生的 THP-1 细胞系中的报告基因实验表明，A 等位基因的启动子活性优于 C 等位基因。电泳迁移率变动分析（EMSA）进一步表明，A 基因型比 C 基因型特异性地与更多的核蛋白结合，包括转录因子 Oct-1。此外，共转染编码 Oct-1 和报告基因构建体的质粒表明，Oct-1 增强了 A 等位基因但不是 C 等位基因的启动子活性。总之，我们的数据表明，与更好的胶质母细胞瘤患者生存相关的 rs12553612 SNP 中的 A 等位基因允许 Oct-1 结合，从而允许 IFNA8 转录，而 C 等位基因的患者中不存在这种结合，这提示了 IFNA8 介导的胶质母细胞瘤进展免疫监测的分子机制。
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