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

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

doi:10.1038/onc.2017.403

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

Oncogene. 2018 Feb 22;37(8):1049-1061. doi: 10.1038/onc.2017.403. Epub 2017 Oct 30.

Authors

S-J Zhao¹, Y-Q Jiang¹, N-W Xu¹, Q Li², Q Zhang¹, S-Y Wang¹, J Li², Y-H Wang², Y-L Zhang², S-H Jiang², Y-J Wang¹, Y-J Huang¹, X-X Zhang², G-A Tian², C-C Zhang³, Y-Y Lv³, M Dai⁴, F Liu⁴, R Zhang³, D Zhou¹, Z-G Zhang²

Affiliations

¹ Department of Orthopedics, the Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People's Hospital, Changzhou, Jiangsu, China.
² State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Obstetrics and Gynecology, Fengxian Hospital, Southern Medical University, Shanghai, China.
⁴ Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Bone Neoplasms / genetics
Bone Neoplasms / metabolism
Bone Neoplasms / pathology
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism*
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*
Humans
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
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Invasiveness
Osteosarcoma / genetics
Osteosarcoma / metabolism
Osteosarcoma / pathology*
Tumor Cells, Cultured
Wnt Proteins / genetics
Wnt Proteins / metabolism*
Xenograft Model Antitumor Assays
beta Catenin / genetics
beta Catenin / metabolism*

Substances

Biomarkers, Tumor
CCL5 protein, human
CTNNB1 protein, human
Calcium-Binding Proteins
Chemokine CCL5
Extracellular Matrix Proteins
Frizzled Receptors
LRP5 protein, human
LRP6 protein, human
Low Density Lipoprotein Receptor-Related Protein-5
Low Density Lipoprotein Receptor-Related Protein-6
SPARCL1 protein, human
Wnt Proteins
beta Catenin