Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea; WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul, 03080, Republic of Korea.
Cancer Lett. 2022 Aug 28;542:215735. doi: 10.1016/j.canlet.2022.215735. Epub 2022 May 13.
Ovarian cancer is mostly diagnosed at advantaged stages due to the lack of early diagnostic biomarkers. The common metastasis pattern is characterized by peritoneal dissemination with a formation of malignant ascites. Extracellular vesicles (EVs) are emerging as promising clinical biomarkers in liquid biopsy. Here, we aimed to investigate robust liquid biopsy-based EV miRNA biomarkers for ovarian cancer diagnosis and metastasis regulation. EVs were isolated from malignant ascites and plasma of ovarian cancer patients as well as the benign control counterparts of patients with benign gynecologic diseases. EV small RNA sequencing identified a panel of eight miRNAs (miR-1246, miR-1290, miR-483, miR-429, miR-34b-3p, miR-34c-5p, miR-145-5p, miR-449a) based on dysregulated miRNAs overlapped in the ascites and plasma subset. The ovarian cancer EV miRNA (OCEM) signature developed based on these eight miRNAs demonstrated high diagnostic accuracy in our in-house dataset and multiple public datasets across diverse clinical samples (blood, tissue and urine). In addition, malignant ascites-derived EVs could significantly facilitate the aggressive property of ovarian cancer cells and boost the growth of ascites-derived organoids. Notably, miR-1246 and miR-1290 shuttled in malignant ascites-derived EVs were identified to promote the invasion and migration of ovarian cancer cells through regulating a common target RORα.
卵巢癌由于缺乏早期诊断生物标志物，大多数在晚期才被诊断出来。常见的转移模式是腹膜扩散，伴有恶性腹水的形成。细胞外囊泡（EVs）作为液体活检中的有前途的临床生物标志物正在出现。在这里，我们旨在研究用于卵巢癌诊断和转移调节的稳健液体活检 EV miRNA 生物标志物。从卵巢癌患者的恶性腹水和血浆中以及患有良性妇科疾病的患者的良性对照物中分离出 EV。EV 小 RNA 测序基于重叠的失调 miRNA 确定了一组 8 个 miRNA（miR-1246、miR-1290、miR-483、miR-429、miR-34b-3p、miR-34c-5p、miR-145-5p、miR-449a）。基于这些 8 个 miRNA 开发的卵巢癌 EV miRNA（OCEM）特征在我们的内部数据集和多个不同临床样本（血液、组织和尿液）的公共数据集上均显示出高诊断准确性。此外，恶性腹水衍生的 EV 可显著促进卵巢癌细胞的侵袭性，并促进腹水衍生类器官的生长。值得注意的是，鉴定出在恶性腹水衍生的 EV 中穿梭的 miR-1246 和 miR-1290 通过调节共同靶标 RORα 来促进卵巢癌细胞的侵袭和迁移。
