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.