Department of laboratory medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
Shenzhen Key Laboratory of Viral Oncology, the Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, China.
Cancer Med. 2018 Aug;7(8):3848-3861. doi: 10.1002/cam4.1537. Epub 2018 Jun 28.
The major histocompatibility complex (MHC) is most closely associated with nasopharyngeal carcinoma (NPC), but the complexity of its genome structure has proven challenging for the discovery of causal MHC loci or genes. We conducted a targeted MHC sequencing in 40 Cantonese NPC patients followed by a two-stage replication in 1065 NPC cases and 2137 controls of Southern Chinese descendent. Quantitative RT-PCR analysis (qRT-PCR) was used to detect gene expression status in 108 NPC and 43 noncancerous nasopharyngeal (NP) samples. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to assess the transcription factor binding site. We discovered that a novel SNP rs117565607_A at TRIM26 displayed the strongest association (OR = 1.909, Pcombined = 2.750 × 10 ). We also observed that TRIM26 was significantly downregulated in NPC tissue samples with genotype AA/AT than TT. Immunohistochemistry (IHC) test also found the TRIM26 protein expression in NPC tissue samples with the genotype AA/AT was lower than TT. According to computational prediction, rs117565607 locus was a binding site for the transcription factor Yin Yang 1 (YY1). We observed that the luciferase activity of YY1 which is binding to the A allele of rs117565607 was suppressed. ChIP data showed that YY1 was binding with T not A allele. Significance analysis of microarray suggested that TRIM26 downregulation was related to low immune response in NPC. We have identified a novel gene TRIM26 and a novel SNP rs117565607_A associated with NPC risk by regulating transcriptional process and established a new functional link between TRIM26 downregulation and low immune response in NPC.
主要组织相容性复合体（MHC）与鼻咽癌（NPC）密切相关，但由于其基因组结构复杂，发现因果 MHC 基因座或基因具有挑战性。我们对 40 名广东 NPC 患者进行了靶向 MHC 测序，然后在 1065 名 NPC 病例和 2137 名中国南方后裔对照中进行了两阶段复制。定量 RT-PCR 分析（qRT-PCR）用于检测 108 名 NPC 和 43 名非癌性鼻咽（NP）样本的基因表达状态。荧光素酶报告基因检测和染色质免疫沉淀（ChIP）用于评估转录因子结合位点。我们发现，TRIM26 上的一个新 SNP rs117565607_A 显示出最强的关联（OR=1.909，Pcombined=2.750×10）。我们还观察到，与 TT 基因型相比，AA/AT 基因型的 NPC 组织样本中 TRIM26 显著下调。免疫组织化学（IHC）测试还发现，AA/AT 基因型的 NPC 组织样本中的 TRIM26 蛋白表达低于 TT 基因型。根据计算预测，rs117565607 位点是转录因子 Yin Yang 1（YY1）的结合位点。我们观察到，与 rs117565607 的 A 等位基因结合的 YY1 的荧光素酶活性受到抑制。ChIP 数据显示，YY1 与 T 而不是 A 等位基因结合。基因表达微阵列的显著性分析表明，TRIM26 的下调与 NPC 中的低免疫反应有关。我们通过调节转录过程鉴定了与 NPC 风险相关的新型基因 TRIM26 和新型 SNP rs117565607_A，并建立了 NPC 中 TRIM26 下调与低免疫反应之间的新功能联系。
