Wu Wei, Jing Doudou, Meng Zibo, Hu Binwu, Zhong Binlong, Deng Xiangyu, Jin Xin, Shao Zengwu
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Theranostics. 2020 Feb 3;10(6):2859-2871. doi: 10.7150/thno.41279. eCollection 2020.
: Mesenchymal cell-derived osteosarcoma is a rare malignant bone tumor affecting children and adolescents. PTEN down-regulation or function-loss mutation is associated with the aggressive of osteosarcoma. Explicating the regulatory mechanism of PTEN might highlight new targets for improving the survival rate of osteosarcoma patients. : The clinical relevance of FGD1 was examined by the TCGA data set, Western blotting and immunohistochemistry of osteosarcoma microarray slides. Functional assays, such as the MTS assay, colony formation assay and xenografts, were used to determine the biological role of FGD1 in osteosarcoma. The protein-protein interaction between FGD1 and PTEN was detected via co-immunoprecipitation. The relationship between FGD1 and PD-L1 was examined by Western blot analysis, RT-qPCR and immunohistochemistry. : In this study, analysis of the TCGA data set of sarcomas revealed that FGD1 was over-expressed with the highest P values. Then, we demonstrated that FGD1 was also abnormally up-regulated in osteosarcoma with unfavorable prognosis. Aberrant expressed FGD1 promoted the osteosarcoma tumor cell proliferation and invasion. Moreover, we found that FGD1 was participated in activating PI3K/AKT signaling pathway by interacting with PTEN. Finally, we showed that FGD1 was capable of regulating the tumor immune response via the PTEN/PD-L1 axis in osteosarcoma. : Our data suggested that abnormally over-expressed FGD1 functions as an oncogenic protein to promote osteosarcoma progression through inhibiting PTEN activity and activating PI3K/AKT signaling. Notably, FGD1 increased PD-L1 expression in a PTEN dependent manner and modulated the sensitivity of immune checkpoint-based immunotherapy in osteosarcoma. Thus, FGD1 might be a potential target for improving the survival rate of osteosarcomas.
间充质细胞源性骨肉瘤是一种罕见的恶性骨肿瘤，影响儿童和青少年。PTEN下调或功能丧失突变与骨肉瘤的侵袭性相关。阐明PTEN的调控机制可能会为提高骨肉瘤患者的生存率突出新的靶点。：通过TCGA数据集、骨肉瘤微阵列玻片的蛋白质印迹和免疫组织化学检测FGD1的临床相关性。使用功能测定法，如MTS测定法、集落形成测定法和异种移植，来确定FGD1在骨肉瘤中的生物学作用。通过免疫共沉淀检测FGD1与PTEN之间的蛋白质-蛋白质相互作用。通过蛋白质印迹分析、RT-qPCR和免疫组织化学检测FGD1与PD-L1之间的关系。：在本研究中，对肉瘤的TCGA数据集分析显示FGD1的表达过高，P值最高。然后，我们证明FGD1在预后不良的骨肉瘤中也异常上调。异常表达的FGD1促进骨肉瘤肿瘤细胞的增殖和侵袭。此外，我们发现FGD1通过与PTEN相互作用参与激活PI3K/AKT信号通路。最后，我们表明FGD1能够通过骨肉瘤中的PTEN/PD-L1轴调节肿瘤免疫反应。：我们的数据表明，异常过表达的FGD1作为一种致癌蛋白，通过抑制PTEN活性和激活PI3K/AKT信号来促进骨肉瘤进展。值得注意的是，FGD1以PTEN依赖的方式增加PD-L1表达，并调节骨肉瘤中基于免疫检查点的免疫治疗的敏感性。因此，FGD1可能是提高骨肉瘤生存率的潜在靶点。
