Abstract
This study explored the role of fibulin-3 in osteosarcoma progression and the possible signaling pathway involved. Fibulin-3 mRNA and protein expression in normal tissue, benign fibrous dysplasia, osteosarcoma, osteosarcoma cell lines (HOS and U-2OS), the normal osteoblastic cell line hFOB, and different invasive subclones was evaluated by immunohistochemistry (IHC) or immunocytochemistry (ICC) and real time reverse transcriptase-polymerase chain reaction (real time qRT-PCR). To assess the role of fibulin-3 in the invasion and metastasis of osteosarcoma cells, lentiviral vectors with fibulin-3 small hairpin RNA (shRNA) and pLVX-fibulin-3 were constructed and used to infect the highly invasive and low invasive subclones. The effects of fibulin-3 knockdown and upregulation on the biological behavior of osteosarcoma cells were investigated by functional in vitro and in vivo assays. The results revealed that fibulin-3 expression was upregulated in osteosarcoma, and was positively correlated with low differentiation, lymph node metastasis, and poor prognosis. Fibulin-3 could promote osteosarcoma cell invasion and metastasis by inducing EMT and activating the Wnt/β-catenin signaling pathway. Collectively, our findings demonstrate that fibulin-3 is a promoter of osteosarcoma development and progression, and suggest a novel therapeutic target for future studies.
Highlights
Osteosarcoma (OS) is the most common malignant primary bone tumor deriving from bone-forming mesenchymal cells, which mainly affects children and adolescents and occurs in long bone extremities, such as the distal femur, the proximal tibia, or the humerus
High fibulin-3 expression was positively associated with low differentiation and lymph node metastasis (Table 1)
We observed that high fibulin-3 expression was associated with poor prognosis of human osteosarcoma, and that fibulin-3 was over-expressed in the highly invasive osteosarcoma cell line and subclone
Summary
Osteosarcoma (OS) is the most common malignant primary bone tumor deriving from bone-forming mesenchymal cells, which mainly affects children and adolescents and occurs in long bone extremities, such as the distal femur, the proximal tibia, or the humerus. The fibulin-3 (FBLN-3) gene, recognized as epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), is a member of the fibulin family of secreted extracellular glycoproteins that is widely expressed in blood vessel walls, and in basement membranes of epithelial and endothelial cells[4]. Fibulin family members are involved in the processes of cell morphology maintenance, growth, adhesion, and movement, both tumour suppressive and oncogenic activities have been proposed in previous researches[7]. In hepatocellular carcinoma[14, 15], gastric cancer[16], lung cancer[17, 18], endometrial carcinoma[19], and nasopharyngeal carcinoma[20], fibulin-3 was down-regulated in cancer tissues and suppressed cancer cell growth and invasion. We investigated the function of fibulin-3 in human osteosarcoma invasion and metastasis, and the the relationship between fibulin-3 and EMT
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