Medical Oncology Department, La Coruña University Hospital, Servicio Galego de Saúde (SERGAS), As Xubias, 84, La Coruña, PC, 15006, Spain.
J Transl Med. 2012 Sep 6;10:186. doi: 10.1186/1479-5876-10-186.
MicroRNAs are aberrantly expressed and correlate with tumourigenesis and the progression of solid tumours. The miR-200 family determines the epithelial phenotype of cancer cells and regulates invasiveness and migration. Thus, we hypothesised that the quantitative detection of the miR-200 family as epithelial-specific microRNAs in the blood could be a useful clinical biomarker for gastric cancer (GC).
We initially validated the expression levels of miR-200a, 200b, 200c and 141 in GC cell lines (n = 2) and blood from healthy controls (n = 19) using real-time quantitative reverse transcription PCR (qRT-PCR). The microarray expression profiles of the miR-200 family in 160 paired samples of non-tumour gastric mucosae and GC were downloaded through ArrayExpress and analysed. MiR-200c was selected for clinical validation. The qRT-PCR prospective assessment of miR-200c was performed using 67 blood samples (52 stage I-IV GC patients and 15 controls); the area under the receiver operating characteristic curve (AUC-ROC) was estimated. The Kaplan-Meier and Breslow-Wilcoxon tests were used to assess the correlation of miR-200c with overall and progression-free survival (OS and PFS). Multivariate analyses were performed using the Cox model.
The miR-200c blood expression levels in GC patients were significantly higher than in normal controls (p = 0.018). The AUC-ROC was 0.715 (p = 0.012). The sensitivity, specificity and accuracy rates of 65.4%, 100% and 73.1%, respectively, were observed. The levels of miR-200c in the blood above the cutoff defined by the ROC curve was found in 17.6% of stage I-II GC patients, 20.6% of stage III patients and 67.7% of stage IV patients (p < 0.001). The miR-200c expression levels were not associated with clinical or pathological characteristics or recent surgical procedures. There was a correlation (p = 0.016) with the number of lymph node metastases and the increased expression levels of miR-200c in blood were significantly associated with a poor OS (median OS, 9 vs 24 months; p = 0.016) and PFS (median PFS, 4 vs 11 months; p = 0.044). Multivariate analyses confirmed that the upregulation of miR-200c in the blood was associated with OS (HR = 2.24; p = 0.028) and PFS (HR = 2.27; p = 0.028), independent of clinical covariates.
These data suggest that increased miR-200c levels are detected in the blood of gastric cancer patients. MiR-200c has the potential to be a predictor of progression and survival.
microRNAs 的表达异常与肿瘤发生和实体瘤的进展相关。miR-200 家族决定了癌细胞的上皮表型，并调节侵袭和迁移。因此，我们假设在血液中定量检测 miR-200 家族作为上皮特异性 microRNAs 可能是胃癌（GC）的一种有用的临床生物标志物。
我们最初使用实时定量逆转录 PCR（qRT-PCR）验证了 GC 细胞系（n=2）和健康对照者（n=19）中 miR-200a、200b、200c 和 141 的表达水平。通过 ArrayExpress 下载了 160 对非肿瘤胃黏膜和 GC 的 miR-200 家族的微阵列表达谱，并进行了分析。选择 miR-200c 进行临床验证。使用 67 个血液样本（52 个 I-IV 期 GC 患者和 15 个对照者）进行 miR-200c 的前瞻性 qRT-PCR 评估；估计了受试者工作特征曲线（ROC）下的面积（AUC-ROC）。采用 Kaplan-Meier 和 Breslow-Wilcoxon 检验评估 miR-200c 与总生存期（OS）和无进展生存期（PFS）的相关性。使用 Cox 模型进行多变量分析。
GC 患者血液中 miR-200c 的表达水平明显高于正常对照组（p=0.018）。AUC-ROC 为 0.715（p=0.012）。观察到 65.4%、100%和 73.1%的灵敏度、特异性和准确率分别为 65.4%、100%和 73.1%。ROC 曲线定义的截定点以上的 miR-200c 血液水平在 17.6%的 I-II 期 GC 患者、20.6%的 III 期患者和 67.7%的 IV 期患者中发现（p<0.001）。miR-200c 的表达水平与临床或病理特征或近期手术程序无关。miR-200c 的表达与淋巴结转移的数量有关，血液中 miR-200c 的高表达与较差的 OS（中位 OS，9 与 24 个月；p=0.016）和 PFS（中位 PFS，4 与 11 个月；p=0.044）显著相关。多变量分析证实，血液中 miR-200c 的上调与 OS（HR=2.24；p=0.028）和 PFS（HR=2.27；p=0.028）相关，与临床协变量无关。
这些数据表明，胃癌患者血液中检测到 miR-200c 水平升高。miR-200c 有可能成为进展和生存的预测因子。
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