Hypoxia-induced circUBR5 and exosomal circUBR5 promotes ovarian cancer progression by miR-17-3p/YAP1/CTGF

A key trait of solid tumors is their hypoxic microenvironment, which strongly influences the course of tumor development. Circular RNAs (circRNAs) exhibit high structural stability compared to linear RNAs and function as key modulators in diverse carcinomas. Nevertheless, the interaction between these factors and hypoxia in ovarian cancer (OC) is still poorly understood. Here, we demonstrate that circUBR5 contributes not only to OC pathogenesis but also to shaping the hypoxic tumor microenvironment. By integrating circRNA microarray profiling of OC cells and their secreted exosomes (EXO) with analysis of GEO datasets, we identified circUBR5 as hypoxia-responsive. Both cell-based and animal assays demonstrated that it acts as an oncogene. Mechanistic investigations employing dual-luciferase reporter experiments showed that circUBR5 directly sponges miR-17-3p, thereby de-repressing the downstream effectors YAP1 and CTGF. Hypoxia significantly upregulated circUBR5 expression in both OC cells and EXO. Functionally, knockdown of circUBR5 led to decreased proliferation of OC cells, increased apoptosis, and impaired endothelial cell-driven angiogenesis. Consistently, in vivo circUBR5 silencing attenuated tumor progression and blood vessel formation in OC xenografts. Our data elucidate a hypoxia-driven axis wherein exosomal circUBR5 promotes OC progression and tumor-endothelial crosstalk via the miR-17-3p/YAP1/CTGF signaling cascade. This study demonstrates the hypoxia/circUBR5/miR-17-3p/YAP1/CTGF axis as a critical regulator of OC malignancy and shows that circUBR5 is a promising therapeutic target.