ANGPTL4-ETV5-CDH5 Signaling Axis: A Novel Pathway Driving Metastasis in Ovarian Cancer

Objective Ovarian cancer (OC) has the highest mortality among gynecologic malignancies. Angiopoietin-like protein 4 (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. Methods We analyzed ANGPTL4 expression in OC tissues and cell lines using high-throughput sequencing, IHC, and bioinformatics, as well as its correlation with patient prognosis and tumor metastasis. Molecular biology experiments were conducted to investigate the underlying mechanisms by which ANGPTL4 promotes ovarian cancer metastasis, with a focus on its interactions with CDH5, ETV5, the AKT signaling pathway, and MMP2/9. Results ANGPTL4 was significantly upregulated in metastatic OC tissues and associated with worse OS, PFI, and DSS. Functionally, ANGPTL4 enhanced cell migration, invasion, and angiogenesis both in vitro and in vivo. Mechanistically, ANGPTL4 upregulated ETV5, which transcriptionally activated CDH5. Elevated CDH5 then triggered AKT phosphorylation and MMP2/9 expression, promoting metastasis. Conclusion This study is the first to untangle the molecular mechanism by which ANGPTL4 promotes ovarian cancer metastasis via activation of the ETV5/CDH5/p-AKT/MMP9 signaling axis, providing a theoretical foundation for novel therapeutic strategies targeting ANGPTL4 in ovarian cancer.