The hsa_circ_0084050/miR-373-3p Axis Controls Bone Sialoprotein-Induced ADAM9 Upregulation to Drive Lung Cancer Progression and Metastasis

Abstract

Lung cancer carries a high mortality burden, with metastatic dissemination accounting for much of its poor prognosis. Bone sialoprotein (BSP), a matricellular protein belonging to the SIBLING family, has been associated with tumor invasion; nonetheless, its role in lung cancer remains inadequately characterized. Clinical database analysis indicates that BSP is the most critical SIBLING protein associated with lung cancer proliferation and metastasis. Our clinical data also confirmed that BSP levels are higher in metastatic lung cancer compared to non-metastatic cases. We further demonstrate that BSP promotes lung cancer progression and motility through upregulated ADAM9 expression. Mechanistically, we revealed that BSP enhances ADAM9-dependent proliferation and motility via the FAK pathway. In addition, the hsa_circ_0084050/miR-373-3p regulatory axis contributes to BSP-mediated ADAM9 regulation. In an exploratory mouse metastasis model established by caudal artery injection of A549 control or stable BSP-shRNA cells into male BALB/c nude mice, BSP knockdown was associated with a lower metastatic tumor burden. Therefore, BSP may serve as a therapeutic target for limiting lung cancer progression and metastatic dissemination.