Genetic variations in miR-125 family and the survival of non-small cell lung cancer in Chinese population
Genetic variations in miR-125 family and the survival of non-small cell lung cancer in Chinese population
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miR-125家族遗传变异与中国人群非小细胞肺癌生存
DOI：
10.1002/cam4.2073
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发表时间：
2019-05-01
期刊：
影响因子：
4
通讯作者：
Wu，Jianqing
中科院分区：
文献类型：
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作者：
Wu，Shuangshuang;Shen，Wei;Wu，Jianqing
为了探讨miR-125家族功能性单核苷酸多态(SNPs)与非小细胞肺癌(NSCLC)患者生存的关系，我们系统地选择了位于miR-125a、miR-125b-1、miR-125b-2三个前期miRNAs的6个功能性SNPs。COX比例风险回归分析用于估计粗略和调整后的危险比(HR)及其95%可信区间(CI)。报告基因荧光素酶分析检测SNPs与miRNAs转录活性的关系。用实时荧光定量聚合酶链式反应检测miRNAs在不同细胞中的表达。我们发现，在显性模型中，rs2241490(miR-125b-1，G；>A，调整后的HR系数=11.24，95%CI=111.05-1.48，P=0.014；在加性模型中，调整后的HR系数=111.18，95%CI=111.03-1.35，P=0.014)，rs512932(在miR-125b-1，A，>；优势模型：调整后HR=1.25，95%CI=1.05~1.48，P=0.013)和rs8111742(MIR-125A上游，G；>A，优势模型：调整后HR=0.84，95%CI=0.71~1.00，P=0.047)与中国非小细胞肺癌患者的预后相关。三个SNPs的联合分析表明，危险等位基因数(rs2241490-A、rs512932-G和rs8111742-G)与非小细胞肺癌的死亡风险之间存在着基因座剂量模型(Pfor Trend<；0.001)。此外，荧光素酶报告基因检测显示，在293T、SPC-A1和A549细胞系中，rs512932变异体G的荧光素酶活性显著高于A等位基因。此外，miR-125b在肺癌细胞中的表达高于正常肺细胞。我们的研究表明miR-125家族的基因变异与NSCLC患者的生存有关。需要更大规模的基于人群和功能的研究来验证这些发现。
To investigate the associations between the functional single nucleotide polymorphisms (SNPs) in the miR‐125 family and the survival of non‐small cell lung cancer (NSCLC) patients, we systematically selected six functional SNPs located in three pre‐miRNAs (miR‐125a, miR‐125b‐1, miR‐125b‐2). Cox proportional hazard regression analyses were conducted to estimate the crude and adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). Reporter gene luciferase assay was performed to examine the relationship between the SNPs and transcriptive activity of the miRNAs. The expression of miRNAs in different cells was detected using quantitative real‐time PCR assay. We found that rs2241490 (upstream of miR‐125b‐1, G > A, adjusted HR = 1.24, 95%CI = 1.05‐1.48,P =0.014, in dominant model; adjusted HR = 1.18, 95%CI = 1.03‐1.35,P= 0.014, in additive model), rs512932 (upstream of miR‐125b‐1, A > G, dominant model: adjusted HR = 1.25, 95%CI = 1.05‐1.48,P =0.013) and rs8111742 (upstream of miR‐125a, G > A, dominant model: adjusted HR = 0.84, 95%CI = 0.71‐1.00,P =0.047) were associated with the prognosis of 1001 Chinese NSCLC patients. The combined analysis of the three SNPs related the number of risk alleles (rs2241490‐A, rs512932‐G and rs8111742‐G) to death risk of NSCLC in a locus‐dosage mode (Pfor trend <0.001). Furthermore, luciferase reporter gene assay showed significantly higher levels of luciferase activity with rs512932 variant G than that with A allele in 293T, SPC‐A1 and A549 cell lines. Besides, miR‐125b was highly expressed in lung cancer cells than the normal lung cell. Our study indicated that genetic variations in miR‐125 family were implicated in the survival of NSCLC patients. Larger population‐based and functional studies are needed to verify these findings.