Abstract
Osteosarcoma, the most common primary malignant bone tumor, shows potent capacity for local invasion and distant metastasis. Connective tissue growth factor (CTGF/CCN2), a secreted protein, binds to integrins, modulates invasive behavior of certain human cancer cells. Effect of CTGF in metastasis of human osteosarcoma is unknown. We found overexpression of CTGF increasing matrix metalloproteinases (MMPs)-2 and MMP-3 expression as well as promoting cell migration. MicroRNA (miRNA) analysis of CTGF-overexpressed osteosarcoma versus control cells probed mechanisms of CTGF-mediated promotion of migration. Among miRNAs regulated by CTGF, miR-519d was most downregulated after CTGF treatment. Co-transfection with miR-519d mimic reversed CTGF-mediated MMPs expression and cell migration. Also, MEK and ERK inhibitors or mutants reduced CTGF-increased cell migration and miR-519d suppression. By contrast, knockdown of CTGF diminished lung metastasis in vivo. Clinical samples indicate CTGF expression as linked with clinical stage and tumor metastasis. Taken together, data show CTGF elevating MMPs expression and subsequently promoting tumor metastasis in human osteosarcoma, down-regulating miR-519d via MEK and ERK pathways, making CTGF a new molecular therapeutic target in osteosarcoma metastasis.
Highlights
Osteosarcoma, the most common primary malignant bone tumor, ranks as main cause of cancer-related death in children and adolescents
The results show that CTGF increases matrix metalloproteinases (MMPs) expression and subsequently promotes tumor metastasis in human osteosarcoma by down-regulating miR-519d through MEK and ERK pathway
The migratory ability was positive corrected with CTGF expression in human osteosarcoma
Summary
Osteosarcoma, the most common primary malignant bone tumor, ranks as main cause of cancer-related death in children and adolescents. It frequently localizes to the distal femur and proximal tibia [1]. With surgery as the sole treatment, diagnosis of osteosarcoma often portended death. Patients had only a 15-20% chance of cure [2]. In the 1980s and 1990s, chemotherapy remarkably augmented survival rates; patients today have about 65-70% chance of 5-year relapse-free survival, if the disease is localized [3]. Other patients will relapse (with pulmonary metastasis) within five years and have undetectable metastatic disease at diagnosis. Pulmonary metastasis is the chief cause of death from osteosarcoma [4]. Patients with metastases have poor prognosis: long-term survival rate of 10-30% [5]. It is necessary to develop novel approaches for treating metastasis, meaning a need to clarify the molecular mechanisms underlying pathogenesis and progression
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