尽管 RANK-LRANK 相互作用对于破骨细胞生成至关重要，但癌细胞侵入骨组织并引发溶骨转移的机制仍不清楚。在这里，我们发现 RelB 的过度激活通过协调白细胞介素 8 (IL-8) 和钙结合蛋白 A4 (S100A4) 促进前列腺癌 (PCa) 溶骨转移。在 PCa 患者血清中研究了促进 PCa 骨转移的因素使用免疫组织化学分析和酶联免疫吸附测定（ELISA）对来自裸鼠的肿瘤组织进行分析。使用 BioStation CT 和 Osteolmage 测定对细胞迁移率和矿化进行量化。通过标准转录分析，包括荧光素酶报告基因反应、定点诱变和染色质免疫沉淀 (ChIP) 测定，研究了高级 PCa 细胞中的相对顺反子。使用多种方法在小鼠中验证 PCa 细胞引发的肿瘤形成、扩张和骨转移，包括原位、骨内和尾动脉植入模型。IL-8 和 S100A4 与患者格里森评分和骨转移相关。 RelB 上调 IL-8，促进不依赖雄激素受体 (AR) 的生长。 RelB-Sp1 相互作用通过激活 Snail 和 Twist 增强上皮间质转化 (EMT)。 RelB-NFAT1c 超级增强子上调细胞骨架和骨转移组织中的 S100A4。 RelB-IL-8-S100A4信号轴被证实可促进裸鼠溶骨转移。RelB-IL-8通过激活炎症信号和灭活AR信号而相互促进EMT。 IL-8 对于引发 PCa 转移至关重要，但不足以驱动骨转移。 IL-8-S100A4 的配合对于转移细胞靶向骨是必要的。RelB 通过上调 IL-8 和抑制 AR 来激活炎症信号传导。 RelB 通过与 NFATC1 合作上调 S100A4。 IL-8 通过激活 Snail 1 和 Twist 1 促进 EMT，而 S100A4 通过钙消耗加剧溶骨转移。 RelB 利用 IL-8 和 S100A4 驱动 PCa 溶骨性转移。© 2024 作者。约翰·威利出版的《临床与转化医学》

Although RANK-LRANK interaction is essential for osteoclastogenesis, the mechanisms by which cancer cells invade bone tissues and initiate osteolytic metastasis remain unclear. Here, we show that the hyperactivation of RelB fosters prostate cancer (PCa) osteolytic metastasis by coordinating interleukin-8 (IL-8) and calcium-binging protein A4 (S100A4).The factors promoting PCa bone metastasis were investigated in sera from PCa patients and tumour tissues derived from nude mice using immunohistochemical analysis and enzyme-linked immunosorbent assays (ELISA). Cell mobility and mineralization were quantified using BioStation CT and Osteolmage assay. The relative cistrome was investigated in advanced PCa cells by standard transcriptional analyses, including the luciferase reporter response, site-directed mutagenesis, and chromatin immunoprecipitation (ChIP) assay. PCa cell-initiated tumour formation, expansion, and bone metastasis were validated in mice using multiple approaches, including orthotopic, intraskeletal, and caudal arterial implantation models.IL-8 and S100A4 correlated with patient Gleason scores and bone metastasis. RelB upregulated IL-8, facilitating androgen receptor (AR)-independent growth. RelB-Sp1 interaction enhanced epithelial-mesenchymal transition (EMT) by activating Snail and Twist. RelB-NFAT1c super-enhancer upregulated S100A4 in the organization of the cytoskeleton and bone metastasis. The RelB-IL-8-S100A4 signalling axis was confirmed to promote osteolytic metastasis in nude mice.RelB-IL-8 reciprocally promoted EMT by activating inflammatory signalling and inactivating AR signalling. IL-8 is essential for provoking PCa metastasis but insufficient to drive bone metastasis. IL-8-S100A4 cooperation was necessary for metastatic cells to target the bone.RelB activates inflammatory signalling by upregulating IL-8 and suppressing AR. RelB upregulates S100A4 by cooperating with NFATC1. IL-8 boosts EMT by activating Snail 1 and Twist 1, and S100A4 exacerbates osteolytic metastasis via calcium consumption. RelB harnesses IL-8 and S100A4 to drive PCa osteolytic metastasis.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.