Cancer-associated fibroblasts (CAFs)-derived exosomes have emerged as a key driver of ovarian cancer (OVCA) tumor progression. The mechanisms behind the specific circular RNA (circRNA) activity encapsulated by CAF-generated exosomes (CAF-exo) requires to be elucidated. Herein, this study selected specific circRNA (hsa_circIFNGR2) molecules and aimed to clarify novel function of CAF-derived exosomal circIFNGR2 on growth, and metastasis of OVCA cells. In this study, we clarified that the exosomes of CAFs originating from human ovarian cancer hindered tumor cell proliferation, metastasis and EMT in vitro. Interestingly, CAFs directly transferred exosomes into OVCA cells to enrich intracellular circIFNGR2 levels. Biologically, activation of exosomal circIFNGR2 blocked cell proliferation, metastasis and EMT. Mechanistically, enhanced circIFNGR2 activated the miR-378/ST5 axis and directly inhibited the malignant evolution of tumor cells. Furthermore, rescue experiments evidenced that circIFNGR2 and ST5 were two essential participants in OVCA, concretely manifested in the co-culture of OVCA cells with exosomes that reversed the effects of intracellular circIFNGR2 and ST5 depletion. Finally, we observed that CAF-exo treatment hindered tumor growth and increased the size and number of metastatic nodules in mice. Our study revealed a previously unknown regulatory pathway whereby CAFs-derived exosomes delivered circIFNGR2 and inhibited the malignant progression of OVCA by circIFNGR2/miR-378/ST5 axis.

中文翻译：

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外泌体传递的 circIFNGR2 通过 miR-378/ST5 轴调节卵巢癌转移。

癌症相关成纤维细胞 (CAF) 衍生的外泌体已成为卵巢癌 (OVCA) 肿瘤进展的关键驱动因素。需要阐明由 CAF 产生的外泌体 (CAF-exo) 包裹的特定环状 RNA (circRNA) 活性背后的机制。在此，本研究选择了特定的 circRNA (hsa_circIFNGR2) 分子，旨在阐明 CAF 来源的外泌体 circIFNGR2 对 OVCA 细胞生长和转移的新功能。在这项研究中，我们阐明了源自人卵巢癌的 CAF 外泌体在体外阻碍了肿瘤细胞的增殖、转移和 EMT。有趣的是，CAFs 直接将外泌体转移到 OVCA 细胞中以丰富细胞内 circIFNGR2 水平。在生物学上，外泌体 circIFNGR2 的激活可阻断细胞增殖、转移和 EMT。从机械上讲，增强的circIFNGR2激活miR-378/ST5轴，直接抑制肿瘤细胞的恶性演化。此外，拯救实验证明 circIFNGR2 和 ST5 是 OVCA 的两个重要参与者，具体表现为 OVCA 细胞与外泌体的共培养，逆转了细胞内 circIFNGR2 和 ST5 耗竭的影响。最后，我们观察到 CAF-exo 治疗阻碍了肿瘤生长并增加了小鼠转移性结节的大小和数量。我们的研究揭示了一种以前未知的调节途径，CAFs 衍生的外泌体通过 circIFNGR2/miR-378/ST5 轴传递 circIFNGR2 并抑制 OVCA 的恶性进展。挽救实验证明，circIFNGR2 和 ST5 是 OVCA 的两个重要参与者，具体表现为 OVCA 细胞与外泌体的共培养，逆转了细胞内 circIFNGR2 和 ST5 耗竭的影响。最后，我们观察到 CAF-exo 治疗阻碍了肿瘤生长并增加了小鼠转移性结节的大小和数量。我们的研究揭示了一种以前未知的调节途径，CAFs 衍生的外泌体通过 circIFNGR2/miR-378/ST5 轴传递 circIFNGR2 并抑制 OVCA 的恶性进展。挽救实验证明，circIFNGR2 和 ST5 是 OVCA 的两个重要参与者，具体表现为 OVCA 细胞与外泌体的共培养，逆转了细胞内 circIFNGR2 和 ST5 耗竭的影响。最后，我们观察到 CAF-exo 治疗阻碍了肿瘤生长并增加了小鼠转移性结节的大小和数量。我们的研究揭示了一种以前未知的调节途径，CAFs 衍生的外泌体通过 circIFNGR2/miR-378/ST5 轴传递 circIFNGR2 并抑制 OVCA 的恶性进展。