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Abstract：
Circulating exosomal microRNAs (miRNAs) have shown great potential for the diagnosis, prognosis, and treatment monitoring of patients with non-small-cell lung cancer (NSCLC). Our main purpose was to determine the clinical value of serum exosomal miR-4497 as a new non-invasive biomarker for NSCLC. The exoRNeasy Kit (QIAGEN, Hilden, Germany) was used to isolate exosomes and exoRNA from the serum of 84 patients with NSCLC (NSCLC group), 30 patients with benign lung lesion (BLL group), and 47 healthy controls. Six serum exosomal miRNAs (Let-7b-5p, miR-122-5p, miR-155-5p, miR-223-3p, miR-320c, and miR-4497) were selected as candidate miRNAs and analyzed using real-time qPCR, among which miR-4497 displayed the most striking differences. Exosomal miR-4497 expressed significantly lower in NSCLC than in BLL patients and healthy controls (P < 0.001). Further investigation showed that miR-4497 was negatively correlated with the malignant characteristics of tumors (tumor size, tumor-node-metastasis [TNM] stage, and distant metastasis) and was an independent tumor suppressor (P < 0.05). According to receiver operating characteristic (ROC) analysis, exosomal miR-4497 independently exhibited excellent diagnostic efficacy, which could be improved by combining it with traditional markers (for identifying tumor size, the area under the curve [AUC] = 0.761; TNM stage, AUC = 0.878; distant metastasis, AUC = 0.895; all P < 0.001). Moreover, longitudinal analysis revealed that exosomal miR-4497 levels increased after chemoradiotherapy (P < 0.001). According to the survival analysis, poor overall survival (OS) and disease-free survival (DFS) were associated with low exosomal miR-4497 levels (P < 0.05). Moreover, exosomal miR-4497 was an independent protective factor affecting DFS (hazard ratio = 0.190, P = 0.009) in the Cox proportional hazards model. Therefore, serum exosomal miR-4497 can be used as a potential biomarker to identify NSCLC and healthy individuals or BLL patients for early screening or as a biomarker for staging and grading, prognosis, and monitoring recurrence, metastasis, and the therapeutic effects in patients with NSCLC.
摘要：
循环外泌体microRNAs（miRNAs）已显示出巨大的诊断潜力，预后,非小细胞肺癌（NSCLC）患者的治疗监测。我们的主要目的是确定血清外泌体miR-4497作为NSCLC新的非侵入性生物标志物的临床价值。exoRNeasy套件(QIAGEN,希尔登,德国）用于从84例NSCLC患者（NSCLC组）的血清中分离外泌体和exoRNA，30例肺良性病变患者（BLL组），和47个健康对照。六个血清外泌体miRNA(Let-7b-5p，miR-122-5p,miR-155-5p,miR-223-3p,miR-320c,和miR-4497）被选择为候选miRNA，并使用实时qPCR进行分析，其中miR-4497显示出最显著的差异.miR-4497在NSCLC中的表达显著低于BLL患者和健康对照组(P<0.001)。进一步研究显示miR-4497与肿瘤的恶性特征呈负相关(肿瘤大小、肿瘤淋巴结转移[TNM]分期，和远处转移），并且是独立的肿瘤抑制因子（P<0.05）。根据接收机工作特性(ROC)分析,外泌体miR-4497独立表现出优异的诊断功效，可以通过将其与传统标记物（用于识别肿瘤大小，曲线下面积[AUC]=0.761；TNM分期，AUC=0.878；远处转移，AUC=0.895；所有P<0.001）。此外，纵向分析显示,放化疗后外泌体miR-4497水平升高(P<0.001).根据生存分析,低总生存期(OS)和无病生存期(DFS)与低外泌体miR-4497水平相关(P<0.05).此外，在Cox比例风险模型中,外泌体miR-4497是影响DFS的独立保护因素(风险比=0.190,P=0.009).因此,血清外泌体miR-4497可用作潜在的生物标志物，以识别NSCLC和健康个体或BLL患者进行早期筛查，或作为分期和分级的生物标志物，预后,监测复发，转移,以及非小细胞肺癌患者的治疗效果。
