Background/Objectives:Alterations in DNA damage repair mechanisms can impair the therapeutic effectiveness of cisplatin. MicroRNAs (miRNAs), key regulators of DNA damage repair processes, have been proposed as promising biomarkers for predicting the response to platinum-based chemotherapy (CT) in non-small cell lung cancer (NSCLC). In this study, by using a bioinformatics approach, we identified six miRNAs, which were differentially expressed (DE) between NSCLC patients characterized as responders and non-responders to platinum-based CT. We further validated the differential expression of the selected miRNAs on tumor and matched normal tissues from patients with resected NSCLC.Methods:Two miRNA microarray expression datasets were retrieved from the Gene Expression Omnibus (GEO) repository, comprising a total of 69 NSCLC patients (N = 69) treated with CT and annotated data from their response to treatment. Differential expression analysis was performed using the Linear Models for Microarray Analysis (Limma) package in R to identify DE miRNAs between responders (N = 33) and non-responders (N = 36). Quantitative real-time PCR (qRT-PCR) was used to assess miRNA expression levels in clinical tissue samples (N = 20).Results:Analysis with the Limma package revealed 112 DE miRNAs between responders and non-responders. A random-effects meta-analysis further identified 24 miRNAs that were consistently up- or downregulated in at least two studies. Survival analysis using the Kaplan–Meier plotter (KM plotter) indicated that 22 of these miRNAs showed significant associations with prognosis in NSCLC. Functional and pathway enrichment analysis revealed that several of the identified miRNAs were linked to key pathways implicated in DNA damage repair, including the p53, Hippo, PI3K and TGF-β signaling pathways. We finally distinguished a six-miRNA signature consisting of miR-26a, miR-29c, miR-34a, miR-30e-5p, miR-30e-3p and miR-497, which were downregulated in non-responders and are involved in at least three DNA damage repair pathways. Comparative expression analysis on tumor and matched normal tissues from surgically treated NSCLC patients confirmed their differential expression in clinical samples.Conclusions:In summary, we identified a signature of six miRNAs that are suppressed in NSCLC and may serve as a predictor of cisplatin response in NSCLC.
背景/目的：DNA损伤修复机制的改变可能削弱顺铂的治疗效果。作为DNA损伤修复过程的关键调控因子，微小RNA（miRNA）被认为是预测非小细胞肺癌（NSCLC）患者对铂类化疗（CT）反应潜力的生物标志物。本研究通过生物信息学方法，在铂类化疗敏感型与非敏感型NSCLC患者中筛选出六个差异表达（DE）的miRNA，并进一步在手术切除的NSCLC患者肿瘤组织及配对正常组织中验证了这些miRNA的表达差异。 方法：从基因表达综合（GEO）数据库获取两个miRNA微阵列表达数据集，共包含69例接受化疗的NSCLC患者（N=69）及其治疗反应注释数据。使用R语言中的Limma包进行差异表达分析，识别敏感型（N=33）与非敏感型（N=36）患者间的DE miRNA。通过实时定量PCR（qRT-PCR）技术检测临床组织样本（N=20）中的miRNA表达水平。 结果：Limma包分析显示敏感型与非敏感型患者间存在112个DE miRNA。随机效应荟萃分析进一步鉴定出24个在至少两项研究中呈现一致上调或下调趋势的miRNA。Kaplan-Meier生存分析表明其中22个miRNA与NSCLC预后显著相关。功能与通路富集分析显示，部分鉴定出的miRNA与DNA损伤修复关键通路相关，包括p53、Hippo、PI3K和TGF-β信号通路。最终确定由miR-26a、miR-29c、miR-34a、miR-30e-5p、miR-30e-3p和miR-497组成的六分子标志物，这些miRNA在非敏感型患者中表达下调，且参与至少三条DNA损伤修复通路。对手术治疗的NSCLC患者肿瘤组织与配对正常组织的比较表达分析证实了其在临床样本中的差异表达。 结论：本研究鉴定出六个在NSCLC中表达受抑制的miRNA标志物，可能作为预测NSCLC患者顺铂治疗反应的生物标志物。
MicroRNA Expression Analysis and Biological Pathways in Chemoresistant Non-Small Cell Lung Cancer
肿瘤(癌症)患者之家