Background Extracellular matrix metalloproteinase inducer (EMMPRIN), a cell-surface glycoprotein, is overexpressed in several cancer types. EMMPRIN induces a metastatic phenotype by triggering the production of matrix metalloproteinase proteins (MMPs) such as MMP1 and MMP2, and vascular endothelial growth factor (VEGF) in cancer cells and the surrounding stromal cells. The purpose of this study was to investigate the expression and role of EMMPRIN in osteosarcoma. Methods The level of EMMPRIN expression was evaluated using reverse transcriptase polymerase chain reaction (RT-PCR) in 6 tumor-derived osteosarcoma cell lines and compared with that in normal osteoblasts. To study the prognostic significance of EMMPRIN expression, immunohistochemistry was carried out in prechemotherapy biopsies of 54 patients. siRNA knockdown of EMMPRIN in SaOS-2 cells was conducted to explore the role of EMMPRIN. To study the role of EMMPRIN in tumor-stromal interaction in MMP production and invasion, co-culture of SaOS-2 cells with osteoblasts and fibroblasts was performed. Osteosarcoma 143B cells were injected into the tail vein of BALB/c mice and lung metastasis was analyzed. Results EMMRIN mRNA expression was significantly higher in 5 of 6 (83%) tumor-derived cells than in MG63 cells. 90% of specimens (50/54) stained positive for EMMPRIN by immunohistochemistry, and higher expression of EMMPRIN was associated with shorter metastasis-free survival (p = 0.023). Co-culture of SaOS-2 with osteoblasts resulted in increased production of pro-MMP2 and VEGF expression, which was inhibited by EMMPRIN-targeting siRNA. siRNA knockdown of EMMPRIN resulted in decreased invasion. EMMPRIN shRNA-transfected 143B cells showed decreased lung metastasis in vivo. Conclusions Our data suggest that EMMPRIN acts as a mediator of osteosarcoma metastasis by regulating MMP and VEGF production in cancer cells as well as stromal cells. EMMPRIN could serve as a therapeutic target in osteosarcoma.
Backgroud Cancer stem cells (CSCs) are cells characterized by their self-renewal and tumorigenic potential. The purpose of this study was to discover the role of the delta-like factor 1 (DLK1) in sarcoma. Methods mRNA expression of DLK1 from 13 sarcoma cell lines was examined. Isolated CSCs from the tumors were examined using fluorescence-activated cell sorting (FACS) with CD133, the CSC marker, or sphere-forming assay. The relationship between DLK1 and CSCs in sarcoma was examined using cell proliferation and cell invasion assays after they were treated with DLK1 short interfering RNA (siRNA). Results A high expression of DLK1 mRNA was observed in all sarcoma cell lines. However, CSCs were isolated from over expressed sarcomas of the DLK1 gene, and they have shown to be expressed lower than the wild type. The anti-cancer effects of DLK1 siRNA inhibited cell proliferation and invasion in U2OS, A204, and sw872. In addition, treatment with DLK1 siRNA inhibited cell invasion in sw872 CSCs. DLK1 gene induces tumorigenesis in various sarcoma cells and regulates the invasiveness of liposarcoma. These results suggest that DLK1 could serve as a possible therapeutic target for sarcoma. Conclusions Our study showed that the DLK1 gene induces tumorigenesis in various sarcomas and is associated with invasive mechanism in sarcoma. These results suggest DLK1 could serve as a possible therapeutic target in a variety of sarcomas.
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