通过 RelB 协调 IL-8 和 S100A4 深入了解前列腺癌溶骨性转移。

Insight into prostate cancer osteolytic metastasis by RelB coordination of IL-8 and S100A4.

机构信息

Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.

Affiliated Cancer Hospital, Nanjing Medical University, Nanjing, China.

出版信息

Clin Transl Med. 2024 Oct;14(10):e70058. doi: 10.1002/ctm2.70058.

DOI:10.1002/ctm2.70058

PMID:39415352

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11483529/

Abstract

BACKGROUND

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).

METHODS

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.

RESULTS

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.

CONCLUSION

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.

HIGHLIGHTS

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.

摘要

背景

尽管 RANK-L/RANK 相互作用对于破骨细胞的形成至关重要，但癌细胞如何侵犯骨组织并引发溶骨性转移仍不清楚。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）溶骨性转移。

方法

通过免疫组织化学分析和酶联免疫吸附试验（ELISA），在来自 PCa 患者的血清和裸鼠肿瘤组织中研究促进 PCa 骨转移的因素。使用 BioStation CT 和 Osteolmage 测定法量化细胞迁移和矿化。通过标准转录分析（包括荧光素酶报告基因反应、定点突变和染色质免疫沉淀（ChIP）测定）研究晚期 PCa 细胞中的相对染色质组。使用多种方法（包括原位、骨骼内和尾动脉植入模型）在小鼠中验证 PCa 细胞引发的肿瘤形成、扩张和骨转移。

结果

IL-8 和 S100A4 与患者的 Gleason 评分和骨转移相关。RelB 上调了 IL-8，促进了雄激素受体（AR）的独立生长。RelB-Sp1 相互作用通过激活 Snail 和 Twist 增强了上皮-间充质转化（EMT）。RelB-NFAT1c 超级增强子在细胞骨架的组织和骨转移中上调了 S100A4。在裸鼠中证实了 RelB-IL-8-S100A4 信号轴促进溶骨性转移。