1. SPARCL1 suppresses osteosarcoma metastasis and recruits macrophages by activation of canonical WNT/β-catenin signaling through stabilization of the WNT–receptor complex
- Author
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Huang Yj, Ruowen Zhang, Yue Jiang, Lv Yy, Zizhen Zhang, Miao Dai, Yingyi Wang, Jia Li, Shujie Zhao, Sen Wang, Zhang Cc, Yinfang Wang, Qing Li, Shu-Heng Jiang, Zhou D, Yan Zhang, Feng Liu, Guang-Ang Tian, Xin Zhang, Qiang Zhang, and Xu Nw
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Frizzled ,Lung Neoplasms ,Beta-catenin ,Mice, Nude ,Apoptosis ,Bone Neoplasms ,SPARCL1 ,Metastasis ,Mice ,03 medical and health sciences ,Paracrine signalling ,Cell Movement ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Genetics ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Chemokine CCL5 ,Molecular Biology ,beta Catenin ,Cell Proliferation ,Extracellular Matrix Proteins ,Mice, Inbred BALB C ,Osteosarcoma ,biology ,Macrophages ,Calcium-Binding Proteins ,Wnt signaling pathway ,LRP6 ,LRP5 ,medicine.disease ,Xenograft Model Antitumor Assays ,Frizzled Receptors ,Gene Expression Regulation, Neoplastic ,Wnt Proteins ,Low Density Lipoprotein Receptor-Related Protein-5 ,030104 developmental biology ,Low Density Lipoprotein Receptor-Related Protein-6 ,Cancer research ,biology.protein ,Original Article - Abstract
Metastasis significantly reduces the survival rate of osteosarcoma (OS) patients. Therefore, identification of novel targets remains extremely important to prevent metastasis and treat OS. In this report, we show that SPARCL1 is downregulated in OS by epigenetic methylation of promoter DNA. In vitro and in vivo experiments revealed that SPARCL1 inhibits OS metastasis. We further demonstrated that SPARCL1-activated WNT/β-catenin signaling by physical interaction with various frizzled receptors and lipoprotein receptor-related protein 5/6, leading to WNT-receptor complex stabilization. Activation of WNT/β-catenin signaling contributes to the SPARCL1-mediated inhibitory effects on OS metastasis. Furthermore, we uncovered a paracrine effect of SPARCL1 on macrophage recruitment through activated WNT/β-catenin signaling-mediated secretion of chemokine ligand5 from OS cells. These findings suggest that the targeting of SPARCL1 as a new anti-metastatic strategy for OS patients.
- Published
- 2017
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