Transcriptomic analysis of glioblastoma multiforme providing new insights into GPR17 signaling communication

Glioblastoma Multiforme (GBM) is one of the most aggressive malignant tumors in the central nervous system, which arises due to the failure or crosstalk in the signaling networks. GPR17, an orphan G protein-coupled receptor is anticipated to be associated with the biology of the GBM disease progression. In the present study, we have identified the differential expressions of around 170 genes along with GPR17 through the RNA-Seq analysis of 169 GBM samples. Coordinated expression patterns of all other gene products with this receptor were analysed using gene ontology and protein–protein interaction data. Several crucial signaling components and genes that play a significant role in tumor progression have been identified among which GPR17 was found to be significantly interacting with about 30 different pathways. High-throughput molecular docking of GPR17 by homology-based model against differentially expressed proteins, showed effective recognition and binding of PX, SH3, and Ig-like domains besides Gi protein. Pathways of PI3, Src, Ptdn, Ras, cytoplasmic tyrosine kinases, phospholipases, nexins and other proteins possessing these structural domains are identified as critical signaling components of the complex GBM signaling network. Our findings also provide a mechanistic insight of GPR17-T0510-3657 interaction, which potentially regulates the interaction of PX domain and helical mPTS recognition domain-containing proteins. Overall, our results demonstrate that GPR17 mediated signaling networks could be used as a therapeutic target for GBM. Communicated by Ramaswamy H. Sarma

多形性胶质母细胞瘤（Glioblastoma Multiforme, GBM）是中枢神经系统中恶性程度最高的肿瘤之一，其发生源于信号网络的功能异常或串扰。GPR17作为一种孤儿G蛋白偶联受体，被推测与GBM的疾病进展生物学过程相关。本研究通过对169例GBM样本开展RNA测序（RNA-Seq）分析，鉴定出包括GPR17在内的约170个差异表达基因。随后借助基因本体（gene ontology, GO）与蛋白质相互作用数据，分析了该受体与其余所有基因产物的协同表达模式。研究鉴定出多个在肿瘤进展中发挥关键作用的重要信号组分与基因，其中GPR17可与约30条不同的信号通路发生显著相互作用。通过基于同源建模模型的GPR17高通量分子对接，针对差异表达蛋白的分析结果显示，除Gi蛋白外，GPR17还可有效识别并结合PX结构域、SH3结构域以及免疫球蛋白样结构域。包含上述结构域的PI3、Src、Ptdn、Ras、胞质酪氨酸激酶、磷脂酶、连接蛋白（nexins）及其他蛋白的相关通路，被确定为复杂GBM信号网络的关键信号组分。本研究还阐明了GPR17-T0510-3657相互作用的机制学内涵，该相互作用可潜在调控含PX结构域与螺旋型mPTS识别结构域的蛋白之间的相互作用。综上，本研究结果证实，GPR17介导的信号网络可作为GBM的治疗靶点。本文由Ramaswamy H. Sarma供稿。