Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Clin Transl Med. 2021 May;11(5):e425. doi: 10.1002/ctm2.425.
Exosomal microRNA (miRNA) as a mediator of intercellular communication plays an essential part in tumor-relevant angiogenesis. Therapy against angiogenesis has been demonstrated to have a remarkable antitumor efficacy in various malignancies, but not as expected in ovarian cancer.
Exosomes were isolated by ultracentrifugation. Exosomal miRNA sequencing and gene function experiments were used to identify the differential expressed miRNAs in exosomes and their mRNA targets. SKOV3 cell line that stably overexpressed miR-92b-3p was constructed by lentivirus. In vitro, angiogenesis was analyzed by tube formation assay and migration assay. The angiogenic and antitumor effects in vivo were assessed in zebrafish and nude mouse models. Combination index was calculated to assess the synergetic inhibition of angiogenesis between miR-92b-3p and Apatinib. Peptides were conjugated with exosomal membranes to obtain engineered exosomes.
Ovarian cancer cell-derived exosomes facilitated the angiogenesis and migration capability of vascular endothelial cells in vitro and in vivo. The expression of miR-92b-3p was much lower in ovarian cancer cell-derived exosomes than that in immortalized ovarian epithelial cell-derived exosomes. The exosomal miR-92b-3p modulated tumor-associated angiogenesis via targeting SOX4. Besides, Peptide-engineered exosomes with overexpressed miR-92b-3p showed the stronger abilities of anti-angiogenesis and antitumor than parental exosomes, whether alone or combined with Apatinib.
Our findings demonstrate the effect and mechanism of exosomal miR-92b-3p from ovarian cancer cells on tumor-associated angiogenesis and the potential of artificially generated exosomes with overexpressed miR-92b-3p to be used as anti-angiogenic agent, which may provide a new approach for anti-angiogenic therapy of ovarian cancer.
外泌体 microRNA（miRNA）作为细胞间通讯的介质，在肿瘤相关血管生成中起着至关重要的作用。抗血管生成治疗已被证明在各种恶性肿瘤中具有显著的抗肿瘤疗效，但在卵巢癌中并非如此。
通过超速离心分离外泌体。通过外泌体 miRNA 测序和基因功能实验，鉴定外泌体中差异表达的 miRNA 及其 mRNA 靶标。通过慢病毒构建稳定过表达 miR-92b-3p 的 SKOV3 细胞系。在体外，通过管形成试验和迁移试验分析血管生成。在斑马鱼和裸鼠模型中评估体内的血管生成和抗肿瘤作用。计算联合指数以评估 miR-92b-3p 和阿帕替尼对血管生成的协同抑制作用。将肽与外泌体膜缀合以获得工程化的外泌体。
卵巢癌细胞来源的外泌体促进了血管内皮细胞在体外和体内的血管生成和迁移能力。与永生化卵巢上皮细胞来源的外泌体相比，卵巢癌细胞来源的外泌体中的 miR-92b-3p 表达水平低得多。外泌体 miR-92b-3p 通过靶向 SOX4 调节肿瘤相关血管生成。此外，与亲本外泌体相比，过表达 miR-92b-3p 的肽工程化外泌体具有更强的抗血管生成和抗肿瘤能力，无论是单独使用还是与阿帕替尼联合使用。
我们的研究结果表明，卵巢癌细胞来源的外泌体 miR-92b-3p 对肿瘤相关血管生成的作用和机制，以及过表达 miR-92b-3p 的人工生成外泌体作为抗血管生成剂的潜力，为卵巢癌的抗血管生成治疗提供了新的途径。
