ABSTRACT
BACKGROUND: Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by chronic progressive stenosis or occlusion of the bilateral internal carotid artery (ICA), the anterior cerebral artery (ACA), and the middle cerebral artery (MCA). MMD is secondary to the formation of an abnormal vascular network at the base of the skull. However, the etiology and pathogenesis of MMD remain poorly understood. METHODS: A competing endogenous RNA (ceRNA) network was constructed by analyzing sample-matched messenger RNA (mRNA), long non-coding RNA (lncRNA), and microRNA (miRNA) expression profiles from MMD patients and control samples. Then, a protein-protein interaction (PPI) network was constructed to identify crucial genes associated with MMD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were employed with the DAVID database to investigate the underlying functions of differentially expressed mRNAs (DEmRNAs) involved in the ceRNA network. CMap was used to identify potential small drug molecules. RESULTS: A total of 94 miRNAs, 3649 lncRNAs, and 2294 mRNAs were differentially expressed between MMD patients and control samples. A synergistic ceRNA lncRNA-miRNA-mRNA regulatory network was constructed. Core regulatory miRNAs (miR-107 and miR-423-5p) and key mRNAs (STAT5B, FOSL2, CEBPB, and CXCL16) involved in the ceRNA network were identified. GO and KEGG analyses indicated that the DEmRNAs were involved in the regulation of the immune system and inflammation in MMD. Finally, two potential small molecule drugs, CAY-10415 and indirubin, were identified by CMap as candidate drugs for treating MMD. CONCLUSIONS: The present study used bioinformatics analysis of candidate RNAs to identify a series of clearly altered miRNAs, lncRNAs, and mRNAs involved in MMD. Furthermore, a ceRNA lncRNA-miRNA-mRNA regulatory network was constructed, which provides insights into the novel molecular pathogenesis of MMD, thus giving promising clues for clinical therapy.
Subject(s)
Moyamoya Disease/genetics , RNA, Long Noncoding/genetics , Case-Control Studies , Computational Biology , Databases, Nucleic Acid , Databases, Pharmaceutical , Gene Expression Profiling , Gene Expression Regulation , Gene Ontology , Gene Regulatory Networks , Humans , Indoles/pharmacology , MicroRNAs/genetics , Molecular Sequence Annotation , Moyamoya Disease/drug therapy , Moyamoya Disease/etiology , Protein Interaction Maps/genetics , RNA, Messenger/genetics , Thiazolidinediones/pharmacologyABSTRACT
Glioblastoma is one of the most malignant brain cancers in adults, and it is a fatal disease because of its untimely pathogenetic location detection, infiltrative growth, and unfavorable prognosis. Unfortunately, multimodal treatment with maximal safe resection, chemotherapy and radiation has not increased the survival rate of patients with glioblastoma. Gene- and molecular-targeted therapy is considered to be a promising anticancer strategy for glioblastoma. The identification of novel potential targets in glioblastoma is of high importance. In this study, we found that both the mRNA and protein levels of diacylglycerol kinase ζ (DGKζ) were significantly higher in glioblastoma tissues than in precancerous lesions. The silencing of DGKζ by lentivirus-delivered shRNA reduced glioblastoma cell proliferation and induced G0/G1 phase arrest. Moreover, knockdown of DGKζ expression in U251 cells markedly reduced in vitro colony formation and in vivo tumorigenic capability. Further study showed that DGKζ inhibition resulted in decreases in cyclin D1, p-AKT and p-mTOR. Moreover, the rescue or overexpression of DGKζ in glioblastoma cells demonstrated the oncogenic function of DGKζ. In conclusion, these studies suggest that the suppression of DGKζ may inhibit the tumor growth of glioblastoma cells with high DGKζ expression. Thus, DGKζ might be a potential therapeutic target in malignant glioblastoma.
