The miR-423-5p/MMP-2 Axis Regulates Nerve Growth Factor-Induced Promotion of Chondrosarcoma Metastasis

Abstract Background: The effects of Nerve growth factor (NGF) in chondrosarcoma are not confirmed, although NGF is capable of promoting the progression and metastasis of several different types of tumors. Here we aim to explore the role of NGF in chondrosarcoma and elucidate how NGF acts.Methods: Immunohistochemistry (IHC)-stained tissue samples from chondrosarcoma patients were stained with NGF and MMP-2 antibodies. Cell migration was examined by Transwell and wound healing assays. The expression levels of MMP-2, microRNA-423-5p (miR-423-5p) were measured by quantitative real-time polymerase chain reaction. MMP-2, FAK, and c-Src protein expression were examined by Western blot assays. The interaction between MMP-2 3’-UTRs and miR-423-5p binding site was explored by luciferase assay. We established the orthotopic in vivo model of chondrosarcoma lung metastasis to further investigate the promoting effects of NGF in metastatic chondrosarcoma.Results: Here, we found that the levels of NGF and matrix metalloproteinase-2 (MMP-2) correlated with tumor stage in patients with chondrosarcoma. NGF facilitated MMP-2-dependent cellular migration in human chondrosarcoma JJ012 cells, while overexpression of NGF enhanced lung metastasis in a mouse model of chondrosarcoma. NGF promoted MMP-2 synthesis and cell migration by inhibiting miR-423-5p expression through the FAK and c-Src signaling cascades. NGF appears to be a worthwhile therapeutic target in the treatment of metastatic chondrosarcoma.Conclusions: Our study has identified that NGF promotes MMP-2-dependent cell migration in human chondrosarcoma tissue by inhibiting miR-423-5p synthesis via the FAK and c-Src signaling cascades