肺癌时骨转移情况常见。骨髓磷蛋白（BSP）是一种非胶原骨基质蛋白，在骨矿化过程和整合素介导的细胞-基质相互作用中发挥着重要作用。值得注意的是，BSP导致肺癌骨转移，但其潜在机制仍不清楚。因此，本研究旨在确定BSP诱导肺癌细胞向骨转移的细胞内信号通路。 Kaplan-Meier，TCGA，GEPIA和GENT2数据库的分析显示，肺组织样本中BSP表达水平高与DECREASED总体存活率（危险比=1.17; p=0.014）及更高的临床疾病分期（F值=2.38，p<0.05）有关。我们还观察到，BSP诱导的基质金属蛋白酶（MMP）-14刺激肺癌细胞通过PI3K / AKT / AP-1信号通路迁移和侵袭。值得注意的是，在暴露于RANKL的RAW 264.7细胞中，BSP促进成骨细胞形成，BSP中和抗体减少了来自肺癌细胞系的加工媒介中的成骨细胞形成。最后，在小鼠注射A549细胞或A549 BSP shRNA细胞8周后，发现BSP表达的敲除显着减少了转移至骨骼。这些结果表明，BSP信号通过其直接的下游靶基因MMP14促进肺部骨转移，揭示了肺癌骨转移的一种新的潜在治疗靶点。版权所有©2023 Elsevier Inc.。

Bone metastases during lung cancer are common. Bone sialoprotein (BSP), a non-collagenous bone matrix protein, plays important functions in bone mineralization processes and in integrin-mediated cell-matrix interactions. Importantly, BSP induces bone metastasis in lung cancer, but the underlying mechanisms remain unclear. This study therefore sought to determine the intracellular signaling pathways responsible for BSP-induced migration and invasion of lung cancer cells to bone. Analyses of the Kaplan-Meier, TCGA, GEPIA and GENT2 databases revealed that high levels of BSP expression in lung tissue samples were associated with significantly decreased overall survival (hazard ratio = 1.17; p = 0.014) and with a more advanced clinical disease stage (F-value = 2.38, p < 0.05). We also observed that BSP-induced stimulation of matrix metalloproteinase (MMP)-14 promoted lung cancer cell migration and invasion via the PI3K/AKT/AP-1 signaling pathway. Notably, BSP promoted osteoclastogenesis in RAW 264.7 cells exposed to RANKL and BSP neutralizing antibody reduced osteoclast formation in conditioned medium (CM) from lung cancer cell lines. Finally, at 8 weeks after mice were injected with A549 cells or A549 BSP shRNA cells, the findings revealed that the knockdown of BSP expression significantly reduced metastasis to bone. These findings suggest that BSP signaling promotes lung bone metastasis via its direct downstream target gene MMP14, which reveals a novel potential therapeutic target for lung cancer bone metastases.Copyright © 2023 Elsevier Inc. All rights reserved.