TGF-β induced PAR-1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone
TGF-β induced PAR-1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone
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TGF-β诱导的PAR-1表达促进骨巨细胞瘤中的肿瘤进展和破骨细胞分化。
DOI：
10.1002/ijc.30862
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发表时间：
2017-10-15
影响因子：
6.4
通讯作者：
Xiao, Jianru
中科院分区：
文献类型：
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作者：
Wang, Ting;Jiao, Jian;Xiao, Jianru
蛋白酶激活受体-1（PAR-1）已被证实是多种肿瘤的癌基因，但其在骨巨细胞瘤（GCT）中的作用尚未见报道。PAR-1在肿瘤诱导破骨细胞生成中的作用机制尚不清楚。在本研究中，我们检测到PAR-1在骨GCT中显著上调，而TGF-β在GCT组织中也过表达，并且可以以剂量和时间依赖性方式促进PAR-1的表达。利用荧光素酶报告基因分析，我们发现TGF-β的两个下游基因Smad 3和Smad 4可以激活PAR-1的启动子，这可能解释了TGF-β诱导PAR-1表达的机制。同时，PAR-1在GCT基质细胞（GCTSCs）的微泡中也有过表达，并可能通过微泡从GCTSCs转运到单核细胞。此外，在GCTSC中通过TALENs敲除PAR-1在体外抑制GCT中的肿瘤生长、血管生成和破骨细胞生成。使用鸡CAM模型，我们进一步表明PAR-1的抑制在体内抑制肿瘤生长和巨细胞形成。利用基因芯片技术，我们检测到了PAR-1下游可能参与破骨细胞生成的基因，这可能部分解释了PAR-1在骨巨细胞瘤中的作用机制。简言之，这些结果首次揭示了TGF-β在PAR-1表达中的上游调节作用，并且PAR-1表达促进骨GCT中的肿瘤生长、血管生成和破骨细胞分化。因此，PAR-1代表了骨GCT的新的潜在治疗靶点。
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-beta 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-beta, Smad3 and Smad4, could activate the promoter of PAR-1, which might explain the mechanism of TGF-beta 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-beta 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.