【摘要】 目的:评估非小细胞肺癌(non-small cell lung cancer,NSCLC)患者血清hsa-miR-107表达水平及临床价值,探究其潜在靶向调控机制。方法:基于全球NSCLC血清miRNA和组织mRNA基因芯片及测序数据集,评估hsa-miR-107综合表达水平,计算标准化平均差(standardized mean difference,SMD),鉴定差异表达miRNA、mRNA。以Kaplan-Meier生存分析评价hsa-miR-107的预后价值。参考萤光素酶报告基因测定和降解组测序结果对hsa-miR-107靶向mRNA进行鉴定,并对hsa-miR-107候选靶基因、NSCLC差异表达基因的交集进行功能注释、蛋白质交互分析。绘制汇总受试者操作特征曲线、Pearson相关系数散点图初步验证hsa-miR-107的靶向枢纽基因。结果:与155份正常人血清样本相比,hsa-miR-107在全球145份NSCLC患者血清样本中表达水平明显降低[SMD=-0.49(-0.73～-0.24)],且对NSCLC有中等区分能力[曲线下面积(area under the curve,AUC)=0.79,95%CI:0.75～0.82]。然而,血清hsa-miR-107高水平表达预示NSCLC患者预后较差(P<0.05,样本数:67)。hsa-miR-107靶基因主要富集于细胞周期通路、DNA复制通路、p53信号通路及细胞衰老通路,其中CCNE1、CDK1基因与hsa-miR-107呈显著负相关且均在NSCLC中呈高表达,被鉴定为hsa-miR-107靶向通路枢纽基因。结论:hsa-miR-107在NSCLC患者血清中低表达且其表达可预示NSCLC患者不良预后。低表达hsa-miR-107可能通过调控细胞周期通路基因CCNE1、CDK1促进NSCLC进展。更多还原

【Abstract】 Objective: To evaluate the expression level and clinical value of serum hsa-miR-107 in patients with non-small cell lung cancer(NSCLC),and to explore its potential targeted regulation mechanisms.Methods:Based on the global NSCLC serum miRNA and tissue mRNA gene chips and sequencing data sets,we assessed the comprehensive expression level of hsa-miR-107 and identified differentially expressed miRNA and mRNA by calculating the standardized mean difference(SMD).The prognostic value of hsa-miR-107 was appraised by Kaplan-Meier survival analysis.The mRNA targets of hsa-miR-107 were identified by referring to the luciferase reporter gene assay and degradome sequencing results.Functional annotation and protein interaction analysis were performed by the intersection genes of hsa-miR-107 candidate targeted genes and NSCLC differentially expressed genes. Summary receiver operating characteristic curve and Pearson correlation coefficient scatter plots were drawn to preliminarily verify the targeted hub genes of hsa-miR-107.Results:Hsa-miR-107 was significantly downregulated in 145 serum samples of global NSCLC patients when compared with 155 normal human serum samples [SMD=-0.49(-0.73 to-0.24)],and had a moderate discriminatory ability [area under the curve(AUC)=0.79,95% CI 0.75 to 0.82] between NSCLC and normal individuals.However,higher expression level of hsa-miR-107 predicted poor prognosis of NSCLC patients(P<0.05,sample sizes:67).Hsa-miR-107 targeted genes were mainly enriched in cell cycle pathway,DNA replication pathway,p53 signaling pathway,and cell senescence pathway.Among them,CCNE1 and CDK1 were significantly negatively correlated with hsa-miR-107 and were highly expressed in NSCLC sample tissues.Therefore,CCNE1 and CDK1 were identified as 2 hub genes in the targeted pathway of hsa-miR-107.Conclusion:hsa-miR-107 is lowly expressed in the serum samples of NSCLC patients and its expression level could predict the poor prognosis of lung adenocarcinoma patients.Lowly expressed hsa-miR-107 may promote NSCLC progression by regulating cell cycle pathway genes(i.e.,CCNE1 and CDK1).更多还原