Abstract
BackgroundRNA binding proteins (RBPs) have been reported to interact with RNAs to regulate gene expression. Circular RNAs (circRNAs) are a type of endogenous non-coding RNAs, which involved in the angiogenesis of tumor. The purpose of this study is to elucidate the potential roles and molecular mechanisms of MOV10 and circ-DICER1 in regulating the angiogenesis of glioma-exposed endothelial cells (GECs).MethodsThe expressions of circ-DICER1, miR-103a-3p and miR-382-5p were detected by real-time PCR. The expressions of MOV10, ZIC4, Hsp90 and PI3K/Akt were detected by real-time PCR or western blot. The binding ability of circ-SHKBP1 and miR-544a / miR-379, ZIC4 and miR-544a / miR-379 were analyzed with Dual-Luciferase Reporter System or RIP experiment. The direct effects of ZIC4 on the Hsp90β promoter were analyzed by the ChIP experiment. The cell viability, migration and tube formation in vitro were detected by CCK-8, Transwell assay and Matrigel tube formation assay. The angiogenesis in vivo was evaluated by Matrigel plug assay. Student’s t-test (two tailed) was used for comparisons between two groups. One-way analysis of variance (ANOVA) was used for multi-group comparisons followed by Bonferroni post-hoc analysis.ResultsThe expressions of RNA binding proteins MOV10, circ-DICER1, ZIC4, and Hsp90β were up-regulated in GECs, while miR103a-3p/miR-382-5p were down-regulated. MOV10 binding circ-DICER1 regulated the cell viability, migration, and tube formation of GECs. And the effects of both MOV10 and circ-DICER1 silencing were better than the effects of MOV10 or circ-DICER1 alone silencing. In addition, circ-DICER1 acts as a molecular sponge to adsorb miR-103a-3p / miR-382-5p and impair the negative regulation of miR-103a-3p / miR-382-5p on ZIC4 in GECs. Furthermore, ZIC4 up-regulates the expression of its downstream target Hsp90β, and Hsp90 promotes the cell viability, migration, and tube formation of GECs by activating PI3K/Akt signaling pathway.ConclusionsMOV10 / circ-DICER1 / miR-103a-3p (miR-382-5p) / ZIC4 pathway plays a vital role in regulating the angiogenesis of glioma. Our findings not only provides novel mechanisms for the angiogenesis of glioma, but also provide potential targets for anti-angiogenesis therapies of glioma.
Highlights
RNA binding proteins (RBPs) have been reported to interact with RNAs to regulate gene expression
Moloney leukemia virus 10 (MOV10) was up-regulated in GECs, knockdown of MOV10 inhibited the angiogenesis of GECs in vitro, and MOV10 combined with circ-DICER1 and regulated its expression The RNA binding protein gene expression profiles were analyzed in astrocyte-exposed endothelial cells (AECs) and U87 glioma-exposed endothelial cells (GECs)
The present study demonstrated that the expressions of RNA binding proteins MOV10, circ-DICER1, Zinc finger of the cerebellum 4 (ZIC4), and Heat shock protein 90 (Hsp90) β were up-regulated in GECs, while miR103a-3p/ miR-382-5p were down-regulated in GECs for the first time
Summary
RNA binding proteins (RBPs) have been reported to interact with RNAs to regulate gene expression. Angiogenesis is the basic pathological feature of malignant tumors, and plays vital roles in the development and progression of tumor [3]. Malignant gliomas have strong vascular invasiveness, and these abnormal blood vessels in structure and function are associated with the development and progression of tumor, which attributes the gene therapy of anti-tumor angiogenesis as one of the hot topics in recent years [4]. RNA-binding proteins (RBPs) play an important role in the regulation of post-transcription levels, including participation in RNA splicing, RNA transport, mRNA stabilization, polyadenosinaction, and intracellular localization [5]. The role of MOV10 has not been reported in the angiogenesis of glioma
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