TGF‐β induced PAR‐1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone |
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| Authors: | Wang Zhou Zhenxi Li Shuai Han Jing Wang Xinghai Yang Quan Huang Zhipeng Wu Wangjun Yan Jianru Xiao |
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| Affiliation: | 1. Department of Bone Tumor Surgery, Changzheng Hospital, Second MilitaryMedical University, Shanghai, China;2. Department of Bone and Soft Tissue Tumor, Shanghai Cancer Center, Fudan University, Shanghai, China |
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| Abstract: | Although protease activated receptor‐1 (PAR‐1) has been confirmed as an oncogene in many cancers, the role of PAR‐1 in giant cell tumor (GCT) of bone has been rarely reported. The mechanism of PAR‐1 in tumor‐induced osteoclastogenesis still remains unclear. In the present study, we detected that PAR‐1 was significantly upregulated in GCT of bone compared to normal tissues, while TGF‐β was also overexpressed in GCT tissues and could promote the expression of PAR‐1 in a dose and time dependent manner. Using the luciferase reporter assay, we found that two downstreams of TGF‐β, Smad3 and Smad4, could activate the promoter of PAR‐1, which might explain the mechanism of TGF‐β induced PAR‐1 expression. Meanwhile, PAR‐1 was also overexpressed in microvesicles from stromal cells of GCT (GCTSCs), and might be transported from GCTSCs to monocytes through microvesicles. In addition, knockout of PAR‐1 by TALENs in GCTSCs inhibited tumor growth, angiogenesis and osteoclastogenesis in GCT in vitro. Using the chick CAM models, we further showed that inhibition of PAR‐1 suppressed tumor growth and giant cell formation in vivo. Using microarray assay, we detected a number of genes involved in osteoclastogenesis as the possible downstreams of PAR‐1, which may partly explain the mechanism of PAR‐1 in GCT. In brief, for the first time, these results reveal an upstream regulatory role of TGF‐β in PAR‐1 expression, and PAR‐1 expression promotes tumor growth, angiogenesis and osteoclast differentiation in GCT of bone. Hence, PAR‐1 represents a novel potential therapeutic target for GCT of bone. |
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| Keywords: | giant cell tumor of bone PAR‐1 TGF‐β microvesicle osteoclast differentiation cell proliferation angiogenesis |
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