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TGF‐β induced PAR‐1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone
Author(s) -
Wang Ting,
Jiao Jian,
Zhang Hao,
Zhou Wang,
Li Zhenxi,
Han Shuai,
Wang Jing,
Yang Xinghai,
Huang Quan,
Wu Zhipeng,
Yan Wangjun,
Xiao Jianru
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30862
Subject(s) - giant cell tumor of bone , cancer research , osteoclast , angiogenesis , stromal cell , biology , microvesicles , transforming growth factor , cell growth , oncogene , cell , giant cell , microbiology and biotechnology , microrna , in vitro , gene , cell cycle , biochemistry , genetics
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.