Midkine drives lung cancer brain metastasis via the NOTCH2/HES1 and PI3K/AKT pathways and serves as a prognostic biomarker
Jinyi Zhou, Bo Li, Kai Ding, Lu Zhang, Songyu Liu, Bin Zeng, Jun Wang, Pin Zuo, Hongping Yuan, Chun Wang, Shujuan Li, Yaodong Fan, Xiaosan SuBackground/Aim
Midkine (MDK), a heparin-binding growth factor, is frequently overexpressed in lung cancer (LC) cells. This study aims to investigate the role of MDK in both LC and lung cancer brain metastasis (LCBM) through proteomic, functional, and in vivo analyses.
Methods
Proteomic analysis was conducted on five paired LC and LCBM samples. Subsequently, we established MDK knockdown and overexpression models to perform in vitro functional studies. We also examined the potential interactions between MDK and various signaling pathways in lung cancer cells. In vivo experiments were carried out to determine whether MDK downregulation could inhibit LCBM. Finally, the correlation between MDK expression and clinical parameters in both LC and LCBM samples was analyzed.
Results
Proteomic profiling of the five paired LC and LCBM samples identified 370 upregulated and 530 downregulated proteins in LCBM, with MDK showing significant overexpression in metastatic samples. MDK overexpression was associated with poor prognosis in lung adenocarcinoma (LUAD) patients and increased migration and invasion in lung cancer cell lines. MDK knockdown (si-MDK) in H1299 cells resulted in reduced proliferation, migration, and invasion, while MDK overexpression (OE-MDK) in H460 and A549 cells promoted these malignant behaviors. Mechanistically, MDK activated the NOTCH2/HES1/NF-κB and PI3K/AKT/CDC42 pathways, driving epithelial-to-mesenchymal transition (EMT) and cytoskeletal remodeling. In vivo, MDK knockdown in H1299 xenografts significantly inhibited brain metastasis and improved survival in nude mice. Clinical validation in 24 LC patients and 23 LCBM patients confirmed elevated MDK expression in metastases. Multivariate analysis identified MDK expression and tumor volume as independent predictors of LCBM.
Conclusion
These findings position MDK as a critical driver of LCBM and a promising therapeutic target for preventing metastatic progression.