Proteomics Analysis of Monocyte-Derived Hepatocyte-Like Cells Identifies Integrin Beta 3 as a Specific Biomarker for Drug-Induced Liver Injury by Diclofenac
Proteomics Analysis of Monocyte-Derived Hepatocyte-Like Cells Identifies Integrin Beta 3 as a Specific Biomarker for Drug-Induced Liver Injury by Diclofenac
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DOI：
10.3389/fphar.2018.00699
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发表时间：
2018-07-04
影响因子：
5.6
通讯作者：
Gerbes, Alexander L.
中科院分区：
文献类型：
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作者：
Dragoi, Diana;Benesic, Andreas;Gerbes, Alexander L.
特异性药物性肝损伤(IDILI)是导致肝移植或死亡的急性肝功能衰竭的主要原因。IDILI的预测和诊断仍然是一个巨大的挑战，因为目前的模型在敏感性、特异性和预后价值方面提供的结果并不令人满意。缺乏适当的IDILI检测工具也损害了可靠生物标记物的发展。在这里，我们报告了一种识别药物特异性生物标志物的新方法。我们结合了单核细胞来源的肝细胞样细胞(MH)能够模拟个体特征的优势，以及基于质谱学的新蛋白质组学技术的优势，以评估双氯芬酸诱导的DILI的潜在生物标志物。我们发现，在来自单个患者的MH细胞中，有超过2700种蛋白质存在差异调节。此后，我们发现，与对照组相比，在双氯芬酸处理的MH细胞中，整合素β3(ITGB3)特异性上调。最后，我们通过对诊断为双氯芬酸-帝力的患者的全血流式细胞术分析和肝活检组织学染色来验证ITGB3。综上所述，我们的结果表明，通过对MH细胞的蛋白质组学分析可以确定候选生物标记物。未来将该方法应用于更广泛的药物，将充分挖掘其开发药物特异性生物标志物的潜力。数据可通过标识符为PXD008918的ProteomeXchange获得。
Idiosyncratic drug-induced liver injury (iDILI) is a major cause of acute liver failure resulting in liver transplantation or death. Prediction and diagnosis of iDILI remain a great challenge, as current models provide unsatisfying results in terms of sensitivity, specificity, and prognostic value. The absence of appropriate tools for iDILI detection also impairs the development of reliable biomarkers. Here, we report on a new method for identification of drug-specific biomarkers. We combined the advantages of monocyte-derived hepatocyte-like (MH) cells, able to mimic individual characteristics, with those of a novel mass spectrometry-based proteomics technology to assess potential biomarkers for Diclofenac-induced DILI. We found over 2,700 proteins differentially regulated in MH cells derived from individual patients. Herefrom, we identified integrin beta 3 (ITGB3) to be specifically upregulated in Diclofenac-treated MH cells from Diclofenac-DILI patients compared to control groups. Finally, we validated ITGB3 by flow cytometry analysis of whole blood and histological staining of liver biopsies derived from patients diagnosed with Diclofenac-DILI. In summary, our results show that biomarker candidates can be identified by proteomics analysis of MH cells. Application of this method to a broader range of drugs in the future will exploit its full potential for the development of drug-specific biomarkers. Data are available via ProteomeXchange with identifier PXD008918.