• Lei Zhu, Fugui Yang, Guangxue Wang, and Qinchuan Li.
• Department of Neurosurgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Department of Thoracic Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
• World Neurosurg. 2022 Oct 1; 166: e369e381e369-e381.

BackgroundCXC motif chemokine receptor type 4 (CXCR4) is an indispensable factor in the process of lung cancer brain metastasis (LCBM). The PI3K/AKT signal pathway is crucial in affecting cell invasion and metastasis and serves as a pivotal regulator in LCBM. However, the relationship between CXCR4 and the PI3K/AKT signal pathway is unclear. This study aimed to explore the underlying mechanisms of CXCR4 and PI3K/AKT in LCBM.MethodsTwo lung cancer cells (A549 and H1299) and cells transfected with short hairpin RNA (shRNA)-CXCR4 were cocultured with normal human astrocyte cells and human brain endothelial (hCMEC/D3) cells to establish a blood-brain barrier model in vitro. The proliferation, migration, and invasion tight junction proteins (claudin-5, occludin, and ZO-1) were examined. Finally, results were verified in a nude mice model.ResultsThe abilities of cell proliferation, migration, and invasion were significantly reduced in A549 and H1299 cells transfected with shRNA-CXCR4 compared with the negative control group. The proteins phosphorylated PI3K and phosphorylated AKT were downregulated in lung cancer cells transfected with shRNA-CXCR4. The proteins claudin-5, occludin, and ZO-1 were upregulated in the A549 and H1299 cells transfected with shRNA-CXCR4. In vivo experiment results confirmed that the knockdown of CXCR4 played a protective role in the process of LCBM.ConclusionsOur findings revealed that CXCR4 promotes LCBM by regulating the PI3K/Akt signal pathway. We also demonstrated that inhibiting CXCR4 could lead to prevention of LCBM. This study provides further rationale for clinical therapy that targets CXCR4/PI3K/AKT.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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