BMPR2 promotes invasion and metastasis via the RhoA-ROCK-LIMK2 pathway in human osteosarcoma cells.
BMPR2 promotes invasion and metastasis via the RhoA-ROCK-LIMK2 pathway in human osteosarcoma cells.
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BMPR2通过RhoA-ROCK-LIMK2通路促进人骨肉瘤细胞的侵袭和转移
DOI：
10.18632/oncotarget.17382
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发表时间：
2017-08-29
期刊：
影响因子：
--
通讯作者：
Guo W
中科院分区：
文献类型：
--
作者：
Wang S;Ren T;Jiao G;Huang Y;Bao X;Zhang F;Liu K;Zheng B;Sun K;Guo W
骨形态发生蛋白受体2 （BMPR2）已在几种类型的癌症中被发现。然而，其在骨肉瘤中的作用在很大程度上是未知的。我们系统地研究了BMPR2在骨肉瘤细胞系、人体组织样本和异种移植模型中的作用。结合生物信息学和临床资料研究BMPR2表达与骨肉瘤患者生存的关系。采用伤口愈合实验和transwell实验检测转染BMPR2后细胞迁移和侵袭能力的变化。此外，下游磷酸化蛋白通过itraq磷酸化蛋白组学分析和western blotting验证。在体内，通过裸鼠原位移植观察BMPR2对143B细胞生长、形成和转移的影响。在这里，我们证明了与正常骨组织相比，BMPR2在大多数骨肉瘤组织中的表达升高。BMPR2表达水平较高的骨肉瘤患者总体生存期较差。143B细胞中BMPR2的缺失显著降低了体外侵袭能力和体内转移潜力。在机制上，我们发现LIM结构域激酶2 （LIMK2）被BMPR2磷酸化和激活，这一事件对于骨肉瘤细胞中BMPR2介导的信号通路的激活至关重要。此外，我们证明BMPR2可以通过RhoA/ROCK途径激活LIMK2，也可以直接与LIMK2相互作用。综上所述，我们的研究表明，BMPR2在体外和体内作为一种前转移癌基因，通过激活RhoA-ROCK-LIMK2途径发挥作用，可能代表了骨肉瘤的潜在治疗靶点。
Bone morphogenetic protein receptor 2 (BMPR2) has been identified in several types of cancer. However, its role in osteosarcoma is largely unknown. We systematically investigated the role of BMPR2 in osteosarcoma cell lines, human tissue samples and xenograft models. The relationship between BMPR2 expression and osteosarcoma patients’ survival was investigated by bioinformatics and clinical data. Wound healing assay and transwell assay were used to detect the changes of cell migration and invasion ability after BMPR2 transfection. In addition, downstream phosphoproteins were analyzed by iTRAQ-based phosphoproteomic analysis and verified by western blotting. In vivo, the effects of BMPR2 on the growth, formation and metastasis of 143B cells were observed by orthotopic transplantation of nude mice. Here, we demonstrated that BMPR2 expression was elevated in a majority of osteosarcoma tissues compared with normal bone tissue. Osteosarcoma patients with greater BMPR2 expressing level showed a poor overall survival. The depletion of BMPR2 in 143B cells markedly reduced the invasive capacity in vitro and metastatic potential in vivo. Mechanistically, we found that LIM domain kinase 2 (LIMK2) was phosphorylated and activated by BMPR2 and that this event was crucial for activation of the BMPR2-mediated signal pathway in osteosarcoma cells. Additionally, we demonstrated that BMPR2 could active LIMK2 through the RhoA/ROCK pathway and could also interact with LIMK2 directly. Taken together, our study revealed that BMPR2 functions as a prometastatic oncogene in vitro and in vivo with the activation of the RhoA-ROCK-LIMK2 pathway and may represent a potential therapeutic target for osteosarcoma.
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