title: CTGF increases matrix metalloproteinases expression and subsequently promotes tumor metastasis in human osteosarcoma through down-regulating miR-519d.
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.
authors.affiliation: Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Hsiao-Chi
authors.initials: HC
authors.lastname: Tsai
authors.forename: Hong-Lin
authors.initials: HL
authors.lastname: Su
authors.forename: Chun-Yin
authors.initials: CY
authors.lastname: Huang
authors.forename: Yi-Chin
authors.initials: YC
authors.lastname: Fong
authors.forename: Chin-Jung
authors.initials: CJ
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan; Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D000328:Adult; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D014162:Transfection; D055815:Young Adult
chemical_list: C526317:CCN2 protein, human; C546194:MIRN519 microRNA, human; D035683:MicroRNAs; D055513:Connective Tissue Growth Factor