LncRNA nuclear‐enriched abundant transcript 1 shuttled by prostate cancer cells‐secreted exosomes initiates osteoblastic phenotypes in the bone metastatic microenvironment via miR‐205‐5p/runt‐related transcription factor 2/splicing factor proline‐ and glutamine‐rich/polypyrimidine tract‐binding protein 2 axis

• Published in: Clinical and translational medicine Vol. 11; no. 8; pp. e493 - n/a
• Main Authors: Mo, Chengqiang, Huang, Bin, Zhuang, Jintao, Jiang, Shuangjian, Guo, Shengjie, Mao, Xiaopeng
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2021; John Wiley and Sons Inc; Wiley
• Subjects: Acids; Animals; Apoptosis; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Clinical medicine; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor Alpha 1 Subunit - metabolism; Disease Models, Animal; Exosomes - genetics; Exosomes - metabolism; extracellular vesicles; Glutamine - metabolism; Humans; Male; mesenchymal stem cells; Metastasis; Mice; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; NEAT1; Osteoblasts - metabolism; osteogenic differentiation; Phenotype; Polypyrimidine Tract-Binding Protein - genetics; Polypyrimidine Tract-Binding Protein - metabolism; Proline - metabolism; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; RNA Splicing Factors; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RUNX2; Transcription factors; Tumor Microenvironment - genetics; prostate cancer; extracellular vesicles; NEAT1; mesenchymal stem cells; osteogenic differentiation; RUNX2
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.493

Prostate cancer (PCa) patients commonly present with osteoblastic‐type bone metastasis. Exosomes derived from tumor cells possess biological significance and can mediate intercellular communication in the tumor microenvironment. Long noncoding RNA (lncRNA) nuclear‐enriched abundant transcript 1 (NEAT1) is also implicated in the stability in tumorigenesis and the development of PCa, but the underlying mechanism remains elusive. Hence, the current study set out to investigate the physiological mechanisms by which exosomes‐encapsulated NEAT1 affects the progression of PCa. First, after isolation, we found PCa cell‐derived exosomes induced the osteogenic differentiation of human bone marrow‐derived mesenchymal stem cells (hBMSCs). Besides, NEAT1 in PCa cells could be transferred into hBMSCs via exosomes. Further gain‐ and loss‐of‐function experimentation revealed that NEAT1 acted as a competing endogenous RNA (ceRNA) of microRNA (miR)‐205‐5p to upregulate the runt‐related transcription factor 2 (RUNX2) levels. Moreover, NEAT1 could promote the RUNX2 expression via the splicing factor proline‐ and glutamine‐rich (SFPQ)/polypyrimidine tract‐binding protein 2 (PTBP2) axis. Functional assays uncovered that NEAT1 shuttled by PCa‐exosomes facilitated the activity of alkaline phosphatase (ALP) and mineralization of extracellular matrix, and continuously upregulated the levels of RUNX2, ALP, alpha‐1 type 1 collagen, and osteocalcin by regulating RUNX2, to induce the osteogenic differentiation of hBMSCs. Furthermore, in vivo experimentation confirmed that upregulated NEAT1 induced osteogenesis. Collectively, our findings indicated that PCa‐derived exosomes‐loaded NEAT1 upregulated RUNX2 to facilitate the osteogenesis of hBMSCs by competitively binding to miR‐205‐5p via the SFPQ/PTBP2 axis, therefore providing a potential therapeutic target to treat osteogenesis of hBMSCs in PCa. PCa cells secrete exosomes containing NEAT1, and NEAT1 exerts effects on osteogenic differentiation of hBMSCs in PCa. NEAT1 shuttled by PCa‐derived exosomes could be transferred into hBMSCs, where NEAT1 exerted inductive properties in osteogenic differentiation of hBMSCs through the upregulation of RUNX2 by competitively binding to miR‐205‐5p and regulating SFPQ/PTBP2 in vitro and in vivo. PCa cells secrete exosomes containing NEAT1, and NEAT1 exerts effects on osteogenic differentiation of hBMSCs in PCa. NEAT1 shuttled by PCa‐derived exosomes could be transferred into hBMSCs, where NEAT1 exerted inductive properties in osteogenic differentiation of hBMSCs through the upregulation of RUNX2 by competitively binding to miR‐205‐5p and regulating SFPQ/PTBP2 in vitro and in vivo.