Extracellular vesicle-shuttled miRNAs as a diagnostic and prognostic biomarker and their potential roles in gallbladder cancer patients.
Extracellular vesicle-shuttled miRNAs as a diagnostic and prognostic biomarker and their potential roles in gallbladder cancer patients.
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DOI：
10.1038/s41598-021-91804-0
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发表时间：
2021-06-10
影响因子：
4.6
通讯作者：
Okada H
中科院分区：
文献类型：
--
作者：
Ueta E;Tsutsumi K;Kato H;Matsushita H;Shiraha H;Fujii M;Matsumoto K;Horiguchi S;Okada H
血清细胞外小泡(EVS)中的循环microRNAs(MiRNAs)是一种很有前途的癌症生物标志物。我们的目的是阐明血清EVS miRNA生物标志物以识别胆囊癌(GBC)患者，并阐明其潜在作用。119份来自胆囊癌和非胆囊癌患者的血清EVS用纯EVS可产生的大小排除层析分离，然后用一个完整的miRNAs阵列和基于RT-qPCR的验证进行分析。利用GBC细胞系研究了已鉴定的miRNAs的功能作用。血清EVS miR-1246和miR-451a在胆囊癌患者中分别显著上调和下调(P = 0.005和P = 0.001)，与其在癌组织中的表达水平一致。联合检测CEA、CA19-9和miR-1246的诊断价值最高(AUC值为0.816；敏感性为72.0%；特异性为90.8%)；COX比例风险模型显示miR-1246是胆囊癌的独立预后标志物(危险比为3.05；P = 为0.017)。在体外，miR-1246促进细胞增殖和侵袭，而miR-451a以MIF、PSMB8和CDKN2D为靶点，抑制细胞增殖和诱导细胞凋亡。综上所述，血清EVS中miR-1246作为诊断和预后标志物具有潜在的应用价值，miR-451a可能成为治疗GBC的新靶点。
Circulating microRNAs (miRNAs) in serum extracellular vesicles (EVs) are a promising biomarker in cancer. We aimed to elucidate the serum EVs miRNA biomarkers to identify patients with gallbladder cancer (GBC) and to clarify their potential roles. One hundred nineteen serum EVs from GBC and non-GBC individuals were isolated by pure-EVs-yieldable size-exclusion chromatography, and then were analyzed using a comprehensive miRNAs array and RT-qPCR-based validation. The functional roles of the identified miRNAs were also investigated using GBC cell lines. Serum EVs miR-1246 and miR-451a were significantly upregulated and downregulated, respectively in GBC patients (P = 0.005 and P = 0.001), in line with their expression levels in cancer tissue according to an in silico analysis. The combination of CEA and CA19-9 with miR-1246 showed the highest diagnostic power (AUC, 0.816; Sensitivity, 72.0%; Specificity, 90.8%), and miR-1246 was an independent prognostic marker of GBC (Hazard ratio, 3.05; P = 0.017) according to a Cox proportional hazards model. In vitro, miR-1246 promoted cell proliferation and invasion, while miR-451a inhibited cell proliferation and induced apoptosis with the targeting of MIF, PSMB8 and CDKN2D. Taken together, miR-1246 in serum EVs has potential application as a diagnostic and prognostic marker and miR-451a may be a novel therapeutic target in GBC.
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