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

Abstract

A chondrosarcoma is a common tumor of the soft tissue and bone that has a high propensity to metastasize to distant organs. Nerve growth factor (NGF) is capable of promoting the progression and metastasis of several different types of tumors although the effects of NGF in a chondrosarcoma are not confirmed. Here, we found that the levels of NGF and matrix metalloproteinase-2 (MMP-2) correlated with the tumor stage in patients with a chondrosarcoma. NGF facilitated the MMP-2-dependent cellular migration in human chondrosarcoma JJ012 cells while the overexpression of NGF enhanced the lung metastasis in a mouse model of a chondrosarcoma. NGF promoted the 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 a metastatic chondrosarcoma.

Nerve growth factor promotes lysyl oxidase-dependent chondrosarcoma cell metastasis by suppressing miR-149-5p synthesis

“…In our previous experiments, we used an established orthotopic mouse model of chondrosarcoma lung metastasis to examine the stimulatory effects of NGF in metastatic chondrosarcoma [ 28 ], which confirmed that NGF promotes chondrosarcoma metastasis in mouse lungs by stimulating MMP-2 expression [ 24 ]. In this study, NGF overexpression in JJ012 cells (JJ012/NGF) promoted high levels of both NGF and LOX protein, which significantly increased the migratory ability of JJ012 cells (Fig.…”

“…In previous IHC tissue array investigations, we have documented higher levels of NGF and MMP-2 expression in patients with higher-grade chondrosarcoma than in those with lower-grade disease [ 24 ]. We also observed in that study a positive significant correlation between MMP-2 and NGF staining intensities of human chondrosarcoma tissue, indicating an association between the levels of these proteins and the progression of chondrosarcoma disease [ 24 ]. In this study, we investigated LOX expression in patients with chondrosarcoma.…”

“…It has also been suggested that NGF plays an integral part in the progression of several types of malignancies, such as ovarian, prostate, and liver cancers [ 19 – 21 ], as well as metastasis in various tumors [ 21 – 23 ]. We have previously reported that NGF promotes MMP-2 expression and chondrosarcoma cell migration by inhibiting miR-423-5p expression through the FAK and c-Src signaling cascades [ 24 ]. We therefore set out to define how NGF could affect chondrosarcoma metastasis, in in vitro and in vivo explorations.…”

Recent Advances in the Treatment of Bone Metastases and Primary Bone Tumors: An Up-to-Date Review

“…However, femur, humerus, and pelvis are also the most frequent sites of dedifferentiated chondrosarcomas, which comprise chondroid and non-chondroid parts often looking like fibroblastic or osteoblastic tissue, indicating two types of mesenchymal differentiation in one tumor [28,29]. Moreover, chondrosarcoma has a high propensity to metastasize to distant organs, especially lungs [30].…”

WISP-3 Stimulates VEGF-C-Dependent Lymphangiogenesis in Human Chondrosarcoma Cells by Inhibiting miR-196a-3p Synthesis

“…Mouse tumor tissues were rehydrated and treated with primary anti-VEGF-C or LYVE-1 antibodies, then incubated with biotin-labeled secondary antibody. The slides were treated with the ABC Kit (Vector Laboratories, Burlingame, CA, USA) according to a previous protocol [30], and then photographed using the microscope. Intra-tumoral lymph vessels were defined as LYVE-1-positive (LYVE-1 + ) vessels that were in close contact with tumor cells or located in the desmoplastic stroma.…”