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Claudin-3 在人胆汁外泌体中的应用作为胆管癌生物标志物的研究。

Utility of Claudin-3 in extracellular vesicles from human bile as biomarkers of cholangiocarcinoma.

机构信息

Department of Gastroenterology, Faculty of Medicine, Yamagata University, 2-2-2 Iidanishi, Yamagata, Yamagata, 990-8595, Japan.

H.U. Group Research Institute G.K., 51 Komiyamachi, Hachioji, Tokyo, 192-0031, Japan.

出版信息

Sci Rep. 2021 Jan 13;11(1):1195. doi: 10.1038/s41598-021-81023-y.

DOI:10.1038/s41598-021-81023-y
PMID:33441949
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7807063/
Abstract

Extracellular vesicles (EVs) are released from all cells. Bile directly contacts bile duct tumor; bile-derived EVs may contain high concentrations of cancer biomarkers. We performed a proteomic analysis of human bile-derived EVs and identified a novel biomarker of cholangiocarcinoma (CCA). EVs were isolated using ultracentrifugation, and chelating agents, ethylenediaminetetraacetic acid and ethylene glycol tetraacetic acid (EDEG) and phosphate buffered saline (PBS) were used as dissolution solutions. Bile was collected from 10 CCA and 10 choledocholithiasis (stones) cases. Proteomic analysis was performed; subsequently, ELISA was performed using the candidate biomarkers in a verification cohort. The vesicles isolated from bile had a typical size and morphology. The expression of exosome markers was observed. RNA was more abundant in the EDEG group. The proportion of microRNA was higher in the EDEG group. EDEG use resulted in the removal of more contaminants. Proteomic analysis identified 166 proteins as CCA-specific. ELISA for Claudin-3 revealed statistically significant difference. The diagnostic accuracy was AUC 0.945 and sensitivity and specificity were 87.5%. We report the first use of EDEG in the isolation of EVs from human bile and the proteomic analysis of human bile-derived EV-proteins in CCA. Claudin-3 in bile-derived EVs is a useful biomarker for CCA.

摘要

细胞外囊泡 (EVs) 由所有细胞释放。胆汁直接接触胆管肿瘤；胆汁衍生的 EVs 可能含有高浓度的癌症生物标志物。我们对人胆汁衍生的 EVs 进行了蛋白质组学分析，鉴定出一种新型胆管癌 (CCA) 标志物。使用超速离心法分离 EVs，并使用螯合剂乙二胺四乙酸和乙二醇四乙酸 (EDEG) 和磷酸盐缓冲盐水 (PBS) 作为溶解溶液。从 10 例 CCA 和 10 例胆管结石 (结石) 病例中收集胆汁。进行蛋白质组学分析；随后，在验证队列中使用候选生物标志物进行 ELISA。从胆汁中分离出的囊泡具有典型的大小和形态。观察到外泌体标志物的表达。EDEG 组中 RNA 更为丰富。EDEG 组中 microRNA 的比例更高。EDEG 的使用去除了更多的污染物。蛋白质组学分析鉴定出 166 种蛋白质为 CCA 特异性。Claudin-3 的 ELISA 显示出统计学上的显著差异。诊断准确性为 AUC 0.945，灵敏度和特异性分别为 87.5%。我们首次报告了在分离人胆汁中的 EVs 中使用 EDEG 以及在 CCA 中进行人胆汁衍生的 EV-蛋白的蛋白质组学分析。胆汁衍生的 EVs 中的 Claudin-3 是 CCA 的有用生物标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/f25f0f4ca08c/41598_2021_81023_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/5002cd7d4c35/41598_2021_81023_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/973b3600fd3e/41598_2021_81023_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/bf808345df71/41598_2021_81023_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/7f3fc5563cd1/41598_2021_81023_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/6a9a13f47d67/41598_2021_81023_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/f25f0f4ca08c/41598_2021_81023_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/5002cd7d4c35/41598_2021_81023_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/973b3600fd3e/41598_2021_81023_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/bf808345df71/41598_2021_81023_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/7f3fc5563cd1/41598_2021_81023_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/6a9a13f47d67/41598_2021_81023_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e18e/7807063/f25f0f4ca08c/41598_2021_81023_Fig6_HTML.jpg

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