| Autor: |
Lanning B; Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff CF14 4YS, UK.; Tissue Microenvironment Group, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff CF14 4YS, UK., Webber J; Tissue Microenvironment Group, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff CF14 4YS, UK.; Institute of Life Science, Swansea University Medical School, Swansea University, Singleton Park, Swansea SA2 8PP, UK., Uysal-Onganer P; School of Life Sciences, College of Liberal Arts and Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK., Jiang WG; Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff CF14 4YS, UK., Clayton A; Tissue Microenvironment Group, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff CF14 4YS, UK., Dart DA; Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff CF14 4YS, UK.; Institute of Medical and Biomedical Education, St George's University of London, Cranmer Terrace, Tooting, London SW17 0RE, UK. |
| Abstrakt: |
Skeletal metastases are the most common form of secondary tumour associated with prostate cancer (PCa). The aberrant function of bone cells neighbouring these tumours leads to the devel-opment of osteoblastic lesions. Communication between PCa cells and bone cells in bone envi-ronments governs both the formation/development of the associated lesion, and growth of the secondary tumour. Using osteoblasts as a model system, we observed that PCa cells and their conditioned medium could stimulate and increase mineralisation and osteoblasts' differentiation. Secreted factors within PCa-conditioned medium responsible for osteoblastic changes included small extracellular vesicles (sEVs), which were sufficient to drive osteoblastogenesis. Using MiR-seq, we profiled the miRNA content of PCa sEVs, showing that miR-16-5p was highly ex-pressed. MiR-16 was subsequently higher in EV-treated 7F2 cells and a miR-16 mimic could also stimulate mineralisation. Next, using RNA-seq of extracellular vesicle (EV)-treated 7F2 cells, we observed a large degree of gene downregulation and an increased mineralisation. Ingenuity® Pathway Analysis (IPA ® ) revealed that miR-16-5p (and other miRs) was a likely upstream effec-tor. MiR-16-5p targets in 7F2 cells, possibly involved in osteoblastogenesis, were included for val-idation, namely AXIN2, PLSCR4, ADRB2 and DLL1. We then confirmed the targeting and dow-regulation of these genes by sEV miR-16-5p using luciferase UTR (untranslated region) reporters. Conversely, the overexpression of PLSCR4, ADRB2 and DLL1 lead to decreased osteoblastogene-sis. These results indicate that miR-16 is an inducer of osteoblastogenesis and is transmitted through prostate cancer-derived sEVs. The mechanism is a likely contributor towards the for-mation of osteoblastic lesions in metastatic PCa. |
