Exosomal circ_0000387 Is Associated With Ovarian Cancer Metastatic Regulation Through IGF2BP3‐Related Signalling and Endothelial VWF Responses

ABSTRACT

This study investigated the context‐dependent roles of circ_0000387 in ovarian cancer (OC) metastasis, focusing on its tumour‐cell‐intrinsic effects and exosome‐mediated tumour–endothelial communication. circRNA sequencing was performed on paired primary and metastatic ovarian cancer tissues to identify metastasis‐associated circRNAs. Gain‐ and loss‐of‐function experiments in SKOV3 cells assessed malignant phenotypes, while CHIRP and RIP assays examined the interaction between circ_0000387 and IGF2BP3. Exosomes were isolated and characterised, and SKOV3–endothelial cell co‐culture experiments evaluated exosome‐associated effects on endothelial VWF responses and tumour‐cell behaviour. An intraperitoneal dissemination mouse model was used for in vivo validation. circ_0000387 was expressed at higher levels in metastatic ovarian cancer tissues than in paired primary tumours. In SKOV3 cells, circ_0000387 interacted with IGF2BP3 and promoted cell viability, invasion, and migration, accompanied by AKT activation, AMPK inhibition, and increased YAP nuclear accumulation. In contrast, circ_0000387‐enriched exosomes increased endothelial VWF secretion and were associated with reduced SKOV3 invasion and migration in an FVIII‐modulated co‐culture context, accompanied by increased AMPK activation and reduced YAP nuclear accumulation. These effects were attenuated by inhibition of exosome release or VWF blockade. In vivo, circ_0000387 overexpression was associated with reduced intraperitoneal dissemination and ascites formation, and these effects were attenuated by Rab27a silencing or VWF neutralisation. circ_0000387 exhibits context‐dependent functions in ovarian cancer, promoting malignant phenotypes within tumour cells through IGF2BP3‐associated AKT/AMPK/YAP signalling while being associated with reduced metastatic activity through exosome‐dependent, VWF‐related tumour–endothelial responses. These findings identify circ_0000387 as a potential regulator of ovarian cancer metastasis warranting further mechanistic and clinical validation.