Journal Article

SPARCL1 suppresses osteosarcoma metastasis and recruits macrophages by activation of canonical WNT/β-catenin signaling through stabilization of the WNT–receptor complex

Xu, N-W, Jiang, Y-Q, Zhang, Q, Zhang, C-C, Zhang, Y-L, Li, J, Zhou, D, Zhang, R, Wang, S-Y, Zhang, Z-G, Zhao, S-J, Jiang, S-H, Lv, Y-Y, Liu, F, Huang, Y-J, Tian, G-A, Wang, Y-H, Dai, M, Zhang, X-X, Li, Q, Wang, Y-J

2018

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 631/67 / 64/60 / Animals / Apoptosis / beta Catenin - genetics / beta Catenin - metabolism / Biomarkers, Tumor - genetics / Biomarkers, Tumor - metabolism / Bone Neoplasms - genetics / Bone Neoplasms - metabolism / Bone Neoplasms - pathology / Calcium-Binding Proteins - genetics / Calcium-Binding Proteins - metabolism / Cell Biology / Cell Movement / Cell Proliferation / Chemokine CCL5 - genetics / Chemokine CCL5 - metabolism / Extracellular Matrix Proteins - genetics / Extracellular Matrix Proteins - metabolism / Frizzled Receptors - genetics / Frizzled Receptors - metabolism / Gene Expression Regulation, Neoplastic / Human Genetics / Humans / Internal Medicine / Low Density Lipoprotein Receptor-Related Protein-5 - genetics / Low Density Lipoprotein Receptor-Related Protein-5 - metabolism / Low Density Lipoprotein Receptor-Related Protein-6 - genetics / Low Density Lipoprotein Receptor-Related Protein-6 - metabolism / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - secondary / Macrophages - metabolism / Macrophages - pathology / Male / Medicine / Medicine & Public Health / Mice / Mice, Inbred BALB C / Mice, Nude / Neoplasm Invasiveness / Oncology / Original / original-article / Osteosarcoma - genetics / Osteosarcoma - metabolism / Osteosarcoma - pathology / Tumor Cells, Cultured / Wnt Proteins - genetics / Wnt Proteins - metabolism / Xenograft Model Antitumor Assays