骨肉瘤发病率逐年上升，95%骨肉瘤患者因转移而死亡，但目前临床缺乏有效的治疗手段。本项目前期研究发现，首先，G蛋白偶联受体137(GPR137)的表达与临床骨肉瘤患者的恶性程度及转移呈正相关；其次，肿瘤相关成纤维细胞(TAFs)可诱导骨肉瘤细胞过表达GPR137并介导酸性微环境，进而促进骨肉瘤细胞的转移。基于前期实验和文献，本研究首创性提出“骨肉瘤微环境中TAFs诱导肿瘤细胞GPR137过表达从而促进骨肉瘤转移”的假说。运用临床样本、基因芯片、蛋白组学等细胞分子生物学和基因敲除小鼠骨肉瘤转移动物模型，探索TAFs如何诱导肿瘤细胞GPR137过表达以及GPR137、骨肉瘤细胞发生上皮-间质转化(EMT)与乳酸代谢在骨肉瘤进程中的相关性及信号通路，进一步诠释GPR137在骨肉瘤转移进程中所扮演的角色，阐述其潜在的作用机制，以期为GPR137可能成为骨肉瘤转移的早期诊断指标提供科学依据。

The incidence of osteosarcoma increases gradually year by year, and 95% of patient died because of tumor metastasis. There is no therapeutic efficacy of the treatment on inhibition osteosarcoma metastasis in clinic. In the previous study, we found that the high expression of G protein coupled receptor 137 (GPR137) appeared to be a common phenomenon of advanced osteosarcoma and could contribute to the poor disease-free survival. Besides, TAFs can induce the GPR137 overexpression of osteosarcoma cells, and GPR137 can enhance cell migration and invasion in osteosarcoma cells in the acidic microenvironment in response to tumor associated fibroblasts (TAFs). Based on the previous study, we put forward the hypothesis of the role of GPR137 induced by TAFs on the osteosarcoma metastasis in the tumor microenvironment. In addition to this, the research project explores how TAFs induce the overexpression of GPR137 in osteosarcoma cells, and the crosstalk among GRP137, epithelial-mesenchymal transition (EMT) and lactate metabolism in the osteosarcoma progress mainly using clinical samples, microarray, proteomics, and knock-in/knock-out nude mice. This project is expected to reveal how GPR137 acts as a promising future diagnostic indicator against osteosarcoma metastasis and to provide pharmacologist with novel molecular drug target.

骨肉瘤发病率逐年上升，95%骨肉瘤患者因转移而死亡，但目前临床缺乏有效的治疗手段。本项目前期研究发现，首先，G蛋白偶联受体137(GPR137)的表达与临床骨肉瘤患者的恶性程度及转移呈正相关；其次，肿瘤相关成纤维细胞(TAFs)可诱导骨肉瘤细胞过表达GPR137并介导酸性微环境，进而促进骨肉瘤细胞的转移。基于本次项目的研究，我们有以下主要成果产出： 1）在多株肿瘤细胞中使用慢病毒载体si-RNA干扰GPR137,我们发现，在Saos-2和U2OS细胞系中，GPR137的表达明显下调了；2）骨肿瘤细胞在缺乏GPR137的情况下，细胞活力和集落形成能力明显受影响，细胞周期也发生了一定程度的改变；3）在干扰掉GPR137的细胞中，AMPK-a，PRAS40和ERK1/2明显下调；4）在人体组织标本中，骨肉瘤组织中GPR137的表达量明显高于周边的正常组织，表达GPR137的患者生存率明显下降。本项目的科学意义在于进一步诠释GPR137在骨肉瘤转移进程中所扮演的角色，阐述其潜在的作用机制，以期为GPR137可能成为骨肉瘤转移的早期诊断指标提供科学依据。