ANGPTL4 promotes metastatic and angiogenic phenotypes in ovarian cancer through an ETV5–CDH5-associated signaling axis

OC has the highest mortality among gynecologic malignancies. ANGPTL4 is highly expressed in several solid tumors, but its role in OC metastasis remains unclear. This study aimed to investigate the regulatory mechanism of ANGPTL4 in OC progression. We analyzed ANGPTL4 expression in OC tissues and cell lines using high-throughput sequencing, IHC, and bioinformatics, and evaluated its correlation with patient prognosis. Molecular biology experiments were conducted to investigate the underlying mechanisms by which ANGPTL4 promotes OC progression. ANGPTL4 was significantly upregulated in metastatic OC tissues and associated with worse OS. Functionally, ANGPTL4 enhanced tumor cell migration and invasion in vitro, and its knockdown was associated with reduced intraperitoneal tumor burden in vivo. Mechanistically, secreted ANGPTL4was associated with activation of the Integrin β1/FAK/STAT3 signaling cascade, which subsequently upregulated the transcription factor ETV5. ETV5 then directly bound to the CDH5 promoter to activate its transcription. Elevated CDH5 was further associated with downstream AKT phosphorylation and MMP2/9 expression. This study identifies a novel ANGPTL4–Integrin β1–ETV5–CDH5 signaling axis in ovarian cancer, through which ANGPTL4 promotes tumor cell invasion and angiogenesis. These findings provide a theoretical foundation for developing novel therapeutic strategies targeting ANGPTL4 in OC.