Bernuzzi F, Marabita F, Lleo A, Carbone M, Mirolo M, Marzioni M, Alpini G, Alvaro D, Boberg K M, Locati M, Torzilli G, Rimassa L, Piscaglia F, He X-S, Bowlus C L, Yang G-X, Gershwin M E, Invernizzi P
Humanitas Clinical and Research Center, Rozzano, MI, Italy.
International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
Clin Exp Immunol. 2016 Jul;185(1):61-71. doi: 10.1111/cei.12776. Epub 2016 May 17.
The diagnosis of primary sclerosing cholangitis (PSC) is difficult due to the lack of sensitive and specific biomarkers, as is the early diagnosis of cholangiocarcinoma (CC), a complication of PSC. The aim of this study was to identify specific serum miRNAs as diagnostic biomarkers for PSC and CC. The levels of 667 miRNAs were evaluated in 90 human serum samples (30 PSC, 30 CC and 30 control subjects) to identify disease-associated candidate miRNAs (discovery phase). The deregulated miRNAs were validated in an independent cohort of 140 samples [40 PSC, 40 CC, 20 primary biliary cirrhosis (PBC) and 40 controls]. Receiver operating characteristic (ROC) curves were established and only miRNAs with an area under the curve (AUC) > 0·70 were considered useful as biomarkers. In the discovery phase we identified the following: 21 miRNAs expressed differentially in PSC, 33 in CC and 26 in both in comparison to control subjects as well as 24 miRNAs expressed differentially between PSC and CC. After the validation phase, miR-200c was found to be expressed differentially in PSC versus controls, whereas miR-483-5p and miR-194 showed deregulated expression in CC compared with controls. We also demonstrate a difference in the expression of miR-222 and miR-483-5p in CC versus PSC. Combination of these specific miRNAs further improved the specificity and accuracy of diagnosis. This study provides a basis for the use of miRNAs as biomarkers for the diagnosis of PSC and CC.
由于缺乏敏感且特异的生物标志物，原发性硬化性胆管炎（PSC）的诊断较为困难，PSC的并发症胆管癌（CC）的早期诊断亦是如此。本研究的目的是鉴定特定的血清微小RNA（miRNA）作为PSC和CC的诊断生物标志物。在90份人类血清样本（30例PSC、30例CC和30例对照受试者）中评估了667种miRNA的水平，以鉴定与疾病相关的候选miRNA（发现阶段）。在一个由140份样本组成的独立队列[40例PSC、40例CC、20例原发性胆汁性肝硬化（PBC）和40例对照]中对失调的miRNA进行了验证。绘制了受试者工作特征（ROC）曲线，只有曲线下面积（AUC）>0.70的miRNA才被认为可作为有用的生物标志物。在发现阶段，我们鉴定出以下结果：与对照受试者相比，21种miRNA在PSC中差异表达，33种在CC中差异表达，26种在两者中均差异表达，以及24种miRNA在PSC和CC之间差异表达。经过验证阶段，发现miR-200c在PSC与对照之间差异表达，而与对照相比，miR-483-5p和miR-194在CC中表达失调。我们还证明了miR-222和miR-483-5p在CC与PSC中的表达存在差异。这些特定miRNA的组合进一步提高了诊断的特异性和准确性。本研究为使用miRNA作为PSC和CC诊断的生物标志物提供了依据。
