Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Oncology. 2021;99(5):336-344. doi: 10.1159/000514131. Epub 2021 Feb 24.
Activating transcription factor 3 (ATF3) plays a significant role in cancer development and progression. We investigated the association between variants in expression quantitative trait loci (eQTLs) within ATF3 binding regions and the prognosis of non-small cell lung cancer (NSCLC) after surgery.
A total of 772 patients with NSCLC who underwent curative surgery were enrolled. Using a public database (http://galaxyproject.org), we selected 104 single nucleotide polymorphisms (SNPs) in eQTLs in the ATF3 binding regions. The association of those SNPs with disease-free survival (DFS) was evaluated.
Among those SNPs, HAX1 rs11265425T>G was associated with significantly worse DFS (aHR = 1.30, 95% CI = 1.00-1.69, p = 0.05), and ME3 rs10400291C>A was associated with significantly better DFS (aHR = 0.66, 95% CI = 0.46-0.95, p = 0.03). Regarding HAX1 rs11265425T>G, the significant association remained only in adenocarcinoma, and the association was significant only in squamous cell carcinoma regarding ME3 rs10400291C>A. ChIP-qPCR assays showed that the two variants reside in active enhancers where H3K27Ac and ATF3 binding occurs. Promoter assays showed that rs11265425 G allele had significantly higher HAX1 promoter activity than T allele. HAX1 RNA expression was significantly higher in tumor than in normal lung, and higher in rs11265425 TG+GG genotypes than in TT genotype. Conversely, ME3 expression was significantly lower in tumor than in normal lung, and higher in rs10400291 AA genotype than in CC+CA genotypes.
In conclusion, this study shows that the functional polymorphisms in ATF3 binding sites, HAX1 rs11265425T>G and ME3 rs10400291C>A are associated with the clinical outcomes of patients in surgically resected NSCLC.
激活转录因子 3（ATF3）在癌症的发生和发展中起着重要作用。我们研究了 ATF3 结合区域内表达数量性状基因座（eQTL）的变异与手术后非小细胞肺癌（NSCLC）患者预后之间的关系。
共纳入 772 例接受根治性手术的 NSCLC 患者。使用公共数据库（http://galaxyproject.org），我们选择了 ATF3 结合区域内 104 个单核苷酸多态性（SNP）的 eQTL。评估这些 SNP 与无病生存期（DFS）的相关性。
在这些 SNP 中，HAX1 rs11265425T>G 与明显较差的 DFS 相关（aHR=1.30，95%CI=1.00-1.69，p=0.05），ME3 rs10400291C>A 与明显较好的 DFS 相关（aHR=0.66，95%CI=0.46-0.95，p=0.03）。对于 HAX1 rs11265425T>G，其显著相关性仅在腺癌中存在，而 ME3 rs10400291C>A 的相关性仅在鳞状细胞癌中存在。ChIP-qPCR 检测表明，这两个变体位于活性增强子中，H3K27Ac 和 ATF3 结合发生在那里。启动子检测表明，rs11265425G 等位基因的 HAX1 启动子活性明显高于 T 等位基因。与正常肺相比，肿瘤中 HAX1 RNA 的表达明显升高，且 rs11265425TG+GG 基因型的表达明显高于 TT 基因型。相反，与正常肺相比，肿瘤中 ME3 的表达明显降低，且 rs10400291AA 基因型的表达明显高于 CC+CA 基因型。
总之，本研究表明，ATF3 结合位点的功能性多态性，HAX1 rs11265425T>G 和 ME3 rs10400291C>A 与手术切除 NSCLC 患者的临床结局相关。
