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

Autor: Sun W; Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.; Affiliated Cancer Hospital, Nanjing Medical University, Nanjing, China.; Department of Thoracic Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China., Xu K; College of Medicine Bowling Green Campus, University of Kentucky, Bowling Green, Kentucky, USA., Li X; Affiliated Cancer Hospital, Nanjing Medical University, Nanjing, China., Qian P; Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.; Affiliated Cancer Hospital, Nanjing Medical University, Nanjing, China., Xu F; Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.; Affiliated Cancer Hospital, Nanjing Medical University, Nanjing, China., Zhang Y; Affiliated Cancer Hospital, Nanjing Medical University, Nanjing, China., Wang X; Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.; Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China., Xu Z; Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China., Ding J; Affiliated Cancer Hospital, Nanjing Medical University, Nanjing, China., Xu X; Affiliated Cancer Hospital, Nanjing Medical University, Nanjing, China., Wei X; Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China., Jiang Q; Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China., Xu Y; Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.; Affiliated Cancer Hospital, Nanjing Medical University, Nanjing, China.; Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Nanjing Medical University, Nanjing, China.; Department of Toxicology and Cancer Biology & Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
Jazyk: angličtina
Zdroj: Clinical and translational medicine [Clin Transl Med] 2024 Oct; Vol. 14 (10), pp. e70058.
DOI: 10.1002/ctm2.70058
Abstrakt: 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.
(© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
Databáze: MEDLINE
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