Oncotarget

Research Papers:

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

Bo Li, Ming Qian, Hao Cao, Qi Jia, Zhipeng Wu, Xinghai Yang, Tianyi Ma, Haifeng Wei, Tianrui Chen and Jianru Xiao _

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Oncotarget. 2017; 8:54966-54977. https://doi.org/10.18632/oncotarget.18629

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Abstract

Bo Li1,*, Ming Qian1,*, Hao Cao2,*, Qi Jia1,*, Zhipeng Wu1, Xinghai Yang1, Tianyi Ma3, Haifeng Wei1, Tianrui Chen1 and Jianru Xiao1

1Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China

2School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China

3Faculty of Psychology and Mental Health, Second Military Medical University, Shanghai, China

*These authors have contributed equally to this work, and all the four authors can be regarded as first authors

Correspondence to:

Jianru Xiao, email: [email protected]

Tianrui Chen, email: [email protected]

Haifeng Wei, email: [email protected]

Keywords: giant cell tumor of bone, ANGPTL4, osteoclast differentiation, cell proliferation, angiogenesis

Received: December 20, 2016     Accepted: May 29, 2017     Published: June 27, 2017

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.


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