Focal Adhesion Kinase Activation Mediates IQ Motif-Containing GTPase-Activating Protein 3-Promoted Lung Metastasis in Osteosarcoma.

Osteosarcoma (OS), the most common primary malignant bone tumor, is characterized by a high metastatic propensity and poor survival, highlighting the urgent need to define the molecular drivers of its progression. Here, bioinformatics and clinical tissue analysis identified aberrantly high expression of IQ motif-containing GTPase-activating protein 3 (IQGAP3) in OS, with its protein level showing a significant negative correlation with patient prognosis. Functional assays demonstrate that IQGAP3 promotes OS cell migration and invasion in vitro and drives lung metastasis in vivo. Transcriptomic analysis links IQGAP3 to the focal adhesion kinase (FAK) signaling pathway. Mechanistically, IQGAP3 directly interacts with FAK and enhances its phosphorylation at Tyr397. Pharmacologic activation of FAK counteracts the suppression of migration and metastasis resulting from IQGAP3 knockdown both in vivo and in vitro. Conversely, FAK inhibition reduces phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, thereby suppressing the GSK-3β/β-catenin axis. Furthermore, Wnt pathway inhibition attenuates IQGAP3-driven cell migration. Finally, the transcription factor zinc finger E-box binding homeobox 1 (ZEB1) was identified as a direct upstream regulator that binds to the IQGAP3 promoter and promotes its expression. Together, the results delineate a novel ZEB1/IQGAP3/FAK/β-catenin signaling axis that critically promotes OS lung metastasis, revealing a potential therapeutic target for intervention.