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

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2024-10-16 DOI:10.1002/ctm2.70058

Wenbo Sun, Kenny Xu, Xiao Li, Peipei Qian, Fan Xu, Yanyan Zhang, Xiumei Wang, Zhi Xu, Jiaji Ding, Xinyu Xu, Xiaowei Wei, Qin Jiang, Yong Xu

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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.

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通过 RelB 协调 IL-8 和 S100A4 透视前列腺癌的溶骨转移

背景虽然 RANK-LRANK 相互作用对破骨细胞生成至关重要，但癌细胞侵入骨组织并启动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）和钙乒蛋白 A4（S100A4）促进了前列腺癌（PCa）的溶骨转移。方法使用免疫组化分析和酶联免疫吸附试验（ELISA）对 PCa 患者血清和裸鼠肿瘤组织中促进 PCa 骨转移的因素进行了研究。使用 BioStation CT 和 Osteolmage 检测法对细胞移动性和矿化进行了量化。通过标准的转录分析，包括荧光素酶报告反应、定点突变和染色质免疫沉淀（ChIP）检测，研究了晚期 PCa 细胞中的相对组蛋白。采用多种方法，包括正位、骨骼内和尾动脉植入模型，在小鼠体内验证了 PCa 细胞引发的肿瘤形成、扩展和骨转移。结果 IL-8 和 S100A4 与患者的格里森评分和骨转移相关。RelB上调IL-8，促进雄激素受体（AR）依赖性生长。RelB-Sp1相互作用通过激活Snail和Twist增强了上皮-间质转化（EMT）。RelB-NFAT1c超级增强子在细胞骨架组织和骨转移中上调S100A4。研究证实，RelB-IL-8-S100A4 信号轴可促进裸鼠的溶骨转移。结论 RelB-IL-8 通过激活炎症信号和失活 AR 信号相互促进 EMT。IL-8对引发PCa转移至关重要，但不足以推动骨转移。IL-8-S100A4合作是转移细胞靶向骨的必要条件。要点 RelB通过上调IL-8和抑制AR激活炎症信号。 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 则通过钙消耗加剧溶骨性转移。 RelB利用IL-8和S100A4驱动PCa溶骨转移。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.