MicroRNA-432-5p regulates sprouting and intussusceptive angiogenesis in osteosarcoma microenvironment by targeting PDGFB

• Published in: Laboratory investigation 2021-08, Vol.101 (8), p.1011-1025
• Main Authors: Vimalraj, Selvaraj, Subramanian, Raghunandhakumar, Saravanan, Sekaran, Arumugam, Balasubramanian, Anuradha, Dhanasekaran
• Format: Article
• Language: English
• Subjects: 13/109; 3' Untranslated regions; 45/77; 631/67/327; 631/80/86/2368; 82/80; 96/106; Angiogenesis; Animals; Antiangiogenics; Aorta; Biomedical materials; Bone cancer; Bone tumors; Cell Line, Tumor; Cell migration; Cell proliferation; Cell viability; Chromosome 5; Endothelial cells; Gene expression; Genes; Growth factors; Humans; Inhibitors; Laboratory Medicine; Medicine; Medicine & Public Health; Metastases; Microenvironments; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Osteosarcoma; Osteosarcoma - genetics; Osteosarcoma - metabolism; Osteosarcoma - pathology; Osteosarcoma cells; Pathology; Platelet-derived growth factor; Proto-Oncogene Proteins c-sis - genetics; Proto-Oncogene Proteins c-sis - metabolism; Reporter gene; Sarcoma; Signaling; Transfection; Tumor Microenvironment - genetics; Tumors; Xenografts; Xenotransplantation; Zebrafish
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-021-00589-3

Osteosarcoma (OS) is a type of bone tumor conferred with high metastatic potential. Attainable growth of tumors necessitates functional vasculature mediated by sprouting angiogenesis (SA) and intussusceptive angiogenesis (IA). However, the regulation of IA and SA is still unclear in OS. To understand the mechanisms adopted by OS to induce angiogenesis, initially, we assessed the expression profile of a set of miRNAs' in both OS cells (SaOS2 and MG63) and normal bone cells. Amongst them, miR-432-5p was found to be highly downregulated in OS. The functional role of miR-432-5p in OS was further analyzed using miR-432-5p mimic/inhibitor. Platelet-derived growth factor-B (PDGFB) was found to be a putative target of miR-432-5p and it was further confirmed that the PDGFB 3′UTR is directly targeted by miR-432-5p using the luciferase reporter gene system. PDGFB was found to be secreted by OS to regulate angiogenesis by targeting the cells in its microenvironment. The conditioned medium obtained from miR-432-5p mimic transfected MG63 and SaOS2 cells decreased cell viability, proliferation, migration, and aorta ring formation in endothelial cells. The miRNA mimic/inhibitor transfected MG63 and SaOS2 cells were placed on SA (day 6) and IA (day 9) phase of CAM development to analyze SA and IA mechanisms. It was found that miR-432-5p mimic transfection in OS promotes the transition of SA to IA which was documented by the angiogenic parameters and SA and IA-associated gene expression. Interestingly, this outcome was also supported by the zebrafish tumor xenograft model. Corroborating these results, it is clear that miR-432-5p expression in OS cells regulates SA and IA by targeting PDGFB genes. We conclude that targeting miR-432-5p/PDGFB signaling can be a potential therapeutic strategy to treat OS along with other existing strategies. MicroRNA-432-5p expression in osteosarcoma cells regulates sprouting and intussusceptive angiogenesis by targeting PDGFB genes. MicroRNA-432-5p/PDGFB signaling can be targeted to treat angiogenesis in osteosarcoma along with other strategies which will further strengthen the effectiveness of antiangiogenic therapy.