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Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
Comprehensive Transcriptomic Analysis and Experimental Validation Identify lncRNA HOXA-AS2/miR-184/COL6A2 as the
Peng-Yu Chen1, Xiao-Dong Li1, Wei-Ning Ma1
1Department of Neurosurgery, Shengjing Hospital Affiliated to China Medical University, Shenyang, People's Republic of China.
Purpose:
The recurrence and metastasis of glioma are closely related to complex regulatory networks among protein-coding genes, lncRNAs and microRNAs. The aim of this study was to investigate core genes, lncRNAs, miRNAs and critical ceRNA regulatory mechanisms, which are involved in lower-grade glioma (LGG) recurrence.
Materials And Methods:
We employed multiple datasets from Chinese Glioma Genome Atlas (CGGA) database and The Cancer Genome Atlas (TCGA) to perform comprehensive transcriptomic analysis. Further in vitro experiments including cell proliferation assay, luciferase reporter assay, and Western blot were performed to validate our results.
Results:
Recurrent LGG and glioblastoma (GBM) showed different transcriptome characteristics with less overlap of differentially expressed protein-coding genes (DEPs), lncRNAs (DELs) and miRNAs (DEMs) compared with primary samples. There were no overlapping gene in ontology (GO) terms related to GBM recurrence in the TCGA and CGGA databases, but there were overlaps associated with LGG recurrence. GO analysis and protein-protein interaction (PPI) network analysis identified three core genes: TIMP1, COL1A1 and COL6A2. By hierarchical cluster analysis of them, LGGs could be clustered as Low_risk and High_risk group. The High_risk group with high expression of TIMP1, COL1A1, and COL6A2 showed worse prognosis. By coexpression networks analysis, competing endogenous RNA (ceRNA) network analysis, cell proliferation assay and luciferase reporter assay, we confirmed that lncRNA HOXA-AS2 functioned as a ceRNA for miR-184 to regulate expression of COL6A2, which induced cell proliferation of low-grade glioma.
Conclusion:
In this study, we revealed a 3-hub protein-coding gene signature to improve prognostic prediction in LGG, and identified a critical ceRNA regulation involved in LGG recurrence.
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