外泌体微小RNA是诊断生物标志物，且可介导肾细胞癌中的细胞间通讯。
Exosomal MicroRNAs Are Diagnostic Biomarkers and Can Mediate Cell-Cell Communication in Renal Cell Carcinoma.
作者信息
Butz Henriett, Nofech-Mozes Roy, Ding Qiang, Khella Heba W Z, Szabó Peter M, Jewett Michael, Finelli Antonio, Lee Jason, Ordon Michael, Stewart Robert, Krylov Sergey, Yousef George M
机构信息
Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
出版信息
Eur Urol Focus. 2016 Jun;2(2):210-218. doi: 10.1016/j.euf.2015.11.006. Epub 2015 Dec 12.
BACKGROUND
Apart from an invasive biopsy, currently no tools are available to confirm the diagnosis of clear cell renal cell carcinoma (ccRCC); this resulted in approximately 30% of patients being diagnosed with metastatic disease.
OBJECTIVE
To determine whether urinary microRNAs (miRNAs) can serve as biomarkers to confirm the diagnosis of ccRCC.
DESIGN, SETTING, AND PARTICIPANTS: Global miRNA expression was assessed in 28 preoperative urine samples from patients with ccRCC and 18 healthy participants. The independent validation set consisted of 81 ccRCC patients, 24 patients with benign lesions, and 33 healthy participants. We extracted both cell-free and exosomal RNA for miRNA expression analysis using miRNA-specific polymerase chain reaction assays. We also investigated exosomal miRNA secretion in cell line models and performed exosome transfer between RCC and endothelial cell types.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Receiver operating characteristic analysis was applied to identify the discrimination power of miRNAs.
RESULTS AND LIMITATIONS
Overall, miR-126-3p combined with miR-449a or with miR-34b-5p could significantly distinguish ccRCC patients from healthy participants (miR-126-3p-miR-449a: area under the curve [AUC]: 0.84; 95% confidence interval [CI], 0.7620-0.9151; p<0.001; miR-126-3p-miR-34b-5p: AUC: 0.79; 95% CI, 0.7013-0.8815; p<0.001). The combination of miR-126-3p and miR-34b-5p was also able to distinguish small renal masses (pT1a, ≤4cm) from healthy controls (AUC: 0.79; 95% CI, 0.6848-0.8980; p<0.001). Using miR-126-3p and miR-486-5p in combination, we were able to differentiate between benign lesions and ccRCC (AUC: 0.85; 95% CI, 0.7295-0.9615; p<0.01). The expression of a number of miRNAs returned to a level comparable with health after surgery. Kidney cancer cell lines were found to secrete exosomal miR-126-3p, miR-17-5p, miR-21-3p, and miR-25-3p, and these miRNAs were found to be internalized by other cell types.
CONCLUSIONS
We identified exosomal miRNAs as potential noninvasive diagnostic urinary biomarkers for ccRCC and provided evidence that miRNAs are secreted by the tumor and can function as a tool for intercellular communication.
PATIENT SUMMARY
We identified urinary microRNAs that can serve as diagnostic biomarkers for clear cell renal cell carcinoma.
背景
除侵入性活检外，目前尚无工具可用于确诊透明细胞肾细胞癌（ccRCC）；这导致约30%的患者被诊断为转移性疾病。
目的
确定尿微小RNA（miRNA）是否可作为确诊ccRCC的生物标志物。
设计、设置和参与者：评估了28例ccRCC患者术前尿液样本和18名健康参与者的整体miRNA表达。独立验证组包括81例ccRCC患者、24例良性病变患者和33名健康参与者。我们使用miRNA特异性聚合酶链反应分析提取无细胞RNA和外泌体RNA进行miRNA表达分析。我们还在细胞系模型中研究了外泌体miRNA分泌，并在肾细胞癌和内皮细胞类型之间进行了外泌体转移。
结局测量和统计分析
应用受试者工作特征分析来确定miRNA的鉴别能力。
结果与局限性
总体而言，miR-126-3p与miR-449a或与miR-34b-5p联合可显著区分ccRCC患者与健康参与者（miR-126-3p-miR-449a：曲线下面积[AUC]：0.84；95%置信区间[CI]，0.7620-0.9151；p<0.001；miR-126-3p-miR-34b-5p：AUC：0.79；95%CI，0.7013-0.8815；p<0.001）。miR-126-3p和miR-34b-5p联合也能够区分小肾肿块（pT1a，≤4cm）与健康对照（AUC：0.79；95%CI，0.6848-0.8980；p<0.001）。联合使用miR-126-3p和miR-486-5p，我们能够区分良性病变和ccRCC（AUC：0.85；95%CI，0.7295-0.9615；p<0.01）。一些miRNA的表达在术后恢复到与健康相当的水平。发现肾癌细胞系分泌外泌体miR-126-3p、miR-17-5p、miR-21-3p和miR-25-3p，并且发现这些miRNA被其他细胞类型内化。
结论
我们确定外泌体miRNA为ccRCC潜在的非侵入性诊断尿液生物标志物，并提供了miRNA由肿瘤分泌且可作为细胞间通讯工具的证据。
患者总结
我们鉴定出可作为透明细胞肾细胞癌诊断生物标志物的尿微小RNA。
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