TGF-β2-induced ANGPTL4 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone

Abstract

Although emerging studies have implicated that Aiopoietin-like 4 Protein (ANGPTL4) is related to the aggressiveness and metastasis of many tumors, the role of ANGPLT4 in giant cell tumor (GCT) of bone was rarely investigated. The mechanism of ANGPLT4 in tumor-induced osteoclastogenesis still remains unclear. In this study, we first demonstrated that ANGPTL4 was highly expressed in GCT compared to normal tissues, while we showed that TGF-β2 released by osteoclasts induced bone resorption could increase the expression of ANGPTL4 in GCTSCs. By using the luciferase reporter assay, we found that two downstreams of TGF-β2, Smad3 and Smad4, could directly activate the promoter of ANGPTL4, which might explain the mechanism of TGF-β2-induced ANGPLT4 expression. Moreover, knockout of ANGPTL4 by TALENs in GCTSCs inhibited tumor growth, angiogenesis and osteoclastogenesis in GCT in vitro. By using the chick chorio-allantoic membrane (CAM) models, we further showed that inhibition of ANGPTL4 suppressed tumor growth and giant cell formation in vivo. In addition, some new pathways involved in ANGPTL4 application were identified through microarray assay, which may partly explain the mechanism of ANGPTL4 in GCT. Taken together, our study for the first time identified the role of ANGPLT4 in GCT of bone, which may provide a new target for the diagnosis and treatment of GCT.