Abstract
Chondrosarcoma is a malignancy of soft tissue and bone that has a high propensity to metastasize to distant organs. Nerve growth factor (NGF) is critical for neuronal cell growth, apoptosis, and differentiation, and also appears to promote the progression and metastasis of several different types of tumors, although the effects of NGF upon chondrosarcoma mechanisms are not very clear. We report that NGF facilitates lysyl oxidase (LOX)-dependent cellular migration and invasion in human chondrosarcoma cells, and that NGF overexpression enhances lung metastasis in a mouse model of chondrosarcoma. NGF-induced stimulation of LOX production and cell motility occurs through the inhibition of miR-149-5p expression, which was reversed by PI3K, Akt, and mTOR inhibitors and their respective short interfering RNAs. Notably, levels of NGF and LOX expression correlated with tumor stage in human chondrosarcoma samples. Thus, NGF appears to be a worthwhile therapeutic target for metastatic chondrosarcoma.
Highlights
Chondrosarcoma is a common malignancy that occurs typically in cartilage-enriched bone [1, 2] that displays a high propensity to metastasize to distant organs [1]
Metastasis of any tumor is characterized by the secretion of proteolytic enzymes such as matrix metalloproteinases (MMPs) and lysyl oxidase (LOX), capable of degrading the extracellular matrix (ECM) and basement membrane [5, 6]
We have previously reported that Nerve growth factor (NGF) promotes MMP-2 expression and chondromechanism in the progression and metastasis of cancer cells [16, 30]
Summary
Chondrosarcoma is a common malignancy that occurs typically in cartilage-enriched bone (e.g., femur, tibia, or pelvis) [1, 2] that displays a high propensity to metastasize to distant organs [1]. It has been suggested that NGF plays an miRNA-associated regulation of LOX expression is a critical integral part in the progression of several types of malignancies, such as ovarian, prostate, and liver cancers [19,20,21], as well as metastasis in various tumors [21,22,23]. A search of five online databases (miRWalk, miRanda, miRMap, RNAhybrid, and TargetScan) for miRNA target prediction indicated that the 3′-UTR region of LOX mRNA contains 14 sarcoma cell migration by inhibiting miR-423-5p expression through the FAK and c-Src signaling cascades [24]. MRNA expression in chondrosarcoma cell lines, and the potential mL) obviously inhibited miR-149-5p synthesis in both chondrorole of NGF in this process. Analyses of the LOX 3′-UTR luciferase plasmids revealed that NGF
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