粘附G蛋白偶联受体116在肺腺癌骨转移中的功能和分子机制研究

GPR116 is one of the members of adhesion GPCR family and has been reported closely related with tumorigenesis and progressing. Through screening of expression and functional assay, we identified the fact that GPR116 could regulate lung adenocarcinoma growth and metastasis in vitro and in vivo. By investigating human lung adenocarcinoma clinical samples, we found that GPR116’s expression level was significantly upregulated and had positive correlation with patients suivival rate. We also found GPR116 could regulate the process of lung adenocarcinoma metastasis through modulating the activity of small GTPase RhoA and influence the transactivation of Parathyroid hormone-like hormone, PTHLH, through the TGF-β-SMAD-mediated signaling pathway. Considerring the preliminary results, we will utilize the in vitro GPR116-knock down stable cell lines and in vivo mice animal models to investigate the function and molecular mechanism of GPR116 in lung adenocarcinoma initiation, progression and metastasis in this project. This project will expand our understanding of GPR116 in lung adenocarcinoma, and figure out new signaling pathways, all of which will provide theoretical evidence for cure and drug research and development of metastazied lung adenocarcinoma.

GPR116是黏附G蛋白偶联受体（adhesion GPCR）家族中的一员，已被证明与肿瘤的发生发展具有密切关系。我们前期的基因表达和功能筛选实验发现GPR116能在体外和体内调控肺腺癌细胞侵袭和转移，并在人类肺腺癌合并骨转移的临床标本中显著高表达。GPR116还能通过调控小G蛋白RhoA活性调节肺腺癌转移过程，且其能通过TGF-β-SMAD信号通路介导的分子机制调控甲状旁腺激素类激素的转录表达。基于前期研究基础，本项目拟利用肺腺癌GPR116干扰/敲低细胞模型和小鼠动物模型，研究GPR116在肺腺癌发生、发展和转移中的功能和分子机理。本项目的实施能揭示GPR116在肺腺癌中的作用，阐明新的信号传导通路，以期为肺腺癌骨转移的治疗和药物研发提供新的理论依据。

肺癌是世界范围内发病率和致死率最高的恶性肿瘤，其中肺腺癌占肺癌总量的50%。GPR116是黏附G蛋白偶联受体（adhesion GPCR）家族中的一员，已被证明与肿瘤的发生发展具有密切关系。在本研究中，我们通过基因表达和功能筛选实验发现GPR116能在体外和体内调控肺腺癌细胞侵袭和转移，并在人类肺腺癌合并骨转移的临床标本中显著高表达。通过收集60例肺癌癌旁、原位和转移癌样本，我们进一步确认了其在肺癌组织中的高表达，及与病人的预后的正相关性。随后的研究还发现，GPR116敲低显著下调肺癌细胞的迁移和侵袭，并调控破骨细胞的分化。在小鼠体内，我们发现缺失GPR116减少了小鼠体内肺转移和小鼠体内骨转移和骨损伤。进一步的机制研究表明，GPR116主要通过TGF-β信号通路影响PTHLH 基因的转录发挥功能。本研究的成果将为肺腺癌骨转移的治疗和药物开发提供一定的理论参考。