Gerloff Dennis, Kewitz-Hempel Stefanie, Hause Gerd, Ehrenreich Jovine, Golle Linda, Kingreen Tim, Sunderkötter Cord
Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
Biocenter, Martin Luther University Halle-Wittenberg, Halle, Germany.
Front Oncol. 2022 Jul 8;12:935816. doi: 10.3389/fonc.2022.935816. eCollection 2022.
Extracellular vesicles (EVs) are important mediators in the intercellular communication, influencing the function and phenotype of different cell types within the tumor micro-milieu and thus promote tumor progression. Since EVs safely transport packages of proteins, lipids and also nucleic acids such as miRNAs, EVs and their cargo can serve as diagnostic and prognostic markers. Therefore, the aim of this study was to investigate EV embedded miRNAs specific for melanoma, which could serve as potential biomarkers. In contrast to previous studies, we not only analysed miRNAs from EVs, but also included the miRNA profiles from the EV-secreting cells to identify candidates as suitable biomarkers. While the characterization of EVs derived from normal melanocytes and melanoma cells showed largely comparable properties with regard to size distribution and expression of protein markers, the NGS analyses yielded marked differences for several miRNAs. While miRNA load of EVs derived from normal human epidermal melanocytes (NHEMs) and melanoma cells were very similar, they were highly different from their secreting cells. By comprehensive analyses, six miRNAs were identified to be enriched in both melanoma cells and melanoma cell-derived EVs. Of those, the accumulation of miR-92b-3p, miR-182-5p and miR-183-5p in EVs could be validated . By functional network generation and pathway enrichment analysis we revealed an association with different tumor entities and signaling pathways contributing melanoma progression. Furthermore, we found that miR-92b-3p, miR-182-5p and miR-183-5p were also enriched in EVs derived from serum of melanoma patients. Our results support the hypothesis that miRNAs derived from EVs can serve as prognostic or diagnostic liquid biopsy markers in melanoma. We identified EV-derived miRNAs and showed that those miRNAs, which were enriched in melanoma cells and EVs, are also found elevated in serum-derived EVs of patients with metastatic melanoma, but not in healthy subjects.
细胞外囊泡（EVs）是细胞间通讯的重要介质，影响肿瘤微环境中不同细胞类型的功能和表型，从而促进肿瘤进展。由于EVs能安全运输蛋白质、脂质以及miRNA等核酸包，EVs及其所载物质可作为诊断和预后标志物。因此，本研究的目的是探究黑色素瘤特异性的EV包埋miRNA，其可作为潜在的生物标志物。与以往研究不同，我们不仅分析了EVs中的miRNA，还纳入了EV分泌细胞的miRNA谱，以确定合适的生物标志物候选物。虽然源自正常黑素细胞和黑色素瘤细胞的EVs在大小分布和蛋白质标志物表达方面表现出大致可比的特性，但NGS分析显示几种miRNA存在显著差异。源自正常人表皮黑素细胞（NHEMs）和黑色素瘤细胞的EVs的miRNA载量非常相似，但与它们的分泌细胞却有很大不同。通过综合分析，鉴定出六种miRNA在黑色素瘤细胞和黑色素瘤细胞衍生的EVs中均富集。其中，miR-92b-3p、miR-182-5p和miR-183-5p在EVs中的积累得到了验证。通过功能网络生成和通路富集分析，我们揭示了其与不同肿瘤实体以及促成黑色素瘤进展的信号通路之间的关联。此外，我们发现miR-92b-3p、miR-182-5p和miR-183-5p在黑色素瘤患者血清衍生的EVs中也有富集。我们的结果支持这样的假设，即源自EVs的miRNA可作为黑色素瘤的预后或诊断性液体活检标志物。我们鉴定出了源自EVs的miRNA，并表明那些在黑色素瘤细胞和EVs中富集的miRNA，在转移性黑色素瘤患者血清衍生的EVs中也升高，但在健康受试者中未升高。
