Dataset Information

FUS/circ_002136/miR-138-5p/SOX13 feedback loop regulates angiogenesis in Glioma.

ABSTRACT: BACKGROUND:Angiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis. METHODS:The expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPON2 were determined using quantitative real-time PCR (qRT-PCR) and western blot. Transient cell transfection was performed using the Lipofectamine 3000 reagent. The RNA-binding protein immunoprecipitation (RNA-IP) and the RNA pull-down assays were used to detect the interaction between FUS and circ_002136. The dual-luciferase reporter assay system was performed to detect the binding sites of circ_002136 and miR-138-5p, miR-138-5p and SOX13. The chromatin immunoprecipitation (ChIP) assays were used to examine the interactions between transcription factor SOX13 and its target proteins . RESULTS:We demonstrated that down-regulation of FUS or circ_002136 dramatically inhibited the viability, migration and tube formation of U87 glioma-exposed endothelial cells (GECs). MiR-138-5p was down-regulated in GECs and circ_002136 functionally targeted miR-138-5p in an RNA-induced silencing complex (RISC). Inhibition of circ_002136, combined with the restoration of miR-138-5p, robustly reduced the angiogenesis of GECs. As a target gene of miR-138-5p, SOX13 was overexpressed in GECs and was proved to be involved in circ_002136 and miR-138-5p-mediated angiogenesis in gliomas. In addition, we found that SOX13 was directly associated with and activated the SPON2 promoter, thereby up-regulating the expression of SPON2 at the transcriptional level. Knockdown of SPON2 suppressed the angiogenesis in GECs. More important, SOX13 activated the FUS promoter and increased its expression, forming a feedback loop. CONCLUSION:Our data suggests that the feedback loop of FUS/circ_002136/miR-138-5p/SOX13 played a crucial role in the regulation of angiogenesis in glioma. This also provides a potential target and an alternative strategy for combined glioma therapy.

SUBMITTER: He Z

PROVIDER: S-EPMC6368736 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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FUS/circ_002136/miR-138-5p/SOX13 feedback loop regulates angiogenesis in Glioma.

He Zhenwei Z Ruan Xuelei X Liu Xiaobai X Zheng Jian J Liu Yunhui Y Liu Libo L Ma Jun J Shao Lianqi L Wang Di D Shen Shuyuan S Yang Chunqing C Xue Yixue Y

Journal of experimental & clinical cancer research : CR 20190208 1

<h4>Background</h4>Angiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis.<h4>Methods</h4>The expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPO ...[more]

PMID: 30736838

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Project description:BackgroundGlioma is the most common and lethal primary brain tumor in adults, and angiogenesis is one of the key factors contributing to its proliferation, aggressiveness, and malignant transformation. However, the discovery of novel oncogenes and the study of its molecular regulating mechanism based on circular RNAs (circRNAs) may provide a promising treatment target in glioma.MethodsBioinformatics analysis, qPCR, western blotting, and immunohistochemistry were used to detect the expression levels of ISL2, miR-342-3p, circRNA ARF1 (cARF1), U2AF2, and VEGFA. Patient-derived glioma stem cells (GSCs) were established for the molecular experiments. Lentiviral-based infection was used to regulate the expression of these molecules in GSCs. The MTS, EDU, Transwell, and tube formation assays were used to detect the proliferation, invasion, and angiogenesis of human brain microvessel endothelial cells (hBMECs). RNA-binding protein immunoprecipitation, RNA pull-down, dual-luciferase reporter, and chromatin immunoprecipitation assays were used to detect the direct regulation mechanisms among these molecules.ResultsWe first identified a novel transcription factor related to neural development. ISL2 was overexpressed in glioma and correlated with poor patient survival. ISL2 transcriptionally regulated VEGFA expression in GSCs and promoted the proliferation, invasion, and angiogenesis of hBMECs via VEGFA-mediated ERK signaling. Regarding its mechanism of action, cARF1 upregulated ISL2 expression in GSCs via miR-342-3p sponging. Furthermore, U2AF2 bound to and promoted the stability and expression of cARF1, while ISL2 induced the expression of U2AF2, which formed a feedback loop in GSCs. We also showed that both U2AF2 and cARF1 had an oncogenic effect, were overexpressed in glioma, and correlated with poor patient survival.ConclusionsOur study identified a novel feedback loop among U2AF2, cARF1, miR-342-3p, and ISL2 in GSCs. This feedback loop promoted glioma angiogenesis, and could provide an effective biomarker for glioma diagnosis and prognostic evaluation, as well as possibly being used for targeted therapy.

Project description:Accumulating evidence has highlighted the potential role of non-coding RNAs (ncRNAs) and upstream open-reading frames (uORFs) in the biological behaviors of glioblastoma. Here, we elucidated the function and possible molecular mechanisms of the effect of some ncRNAs and NR2C2-uORF on the biological behaviors of gliomas. Quantitative real-time PCR was conducted to profile the cell expression of lnc-UCA1 and microRNA-627-5p (miR-627-5p) in glioma tissues and cells. Western blot assay was used to determine the expression levels of NR2C2, SPOCK1, and NR2C2-uORF in glioma tissues and cells. Stable knockdown of lnc-UCA1 or overexpression of miR-627-5p in glioma cell lines (U87 and U251) were established to explore the function of lnc-UCA1 and miR-627-5p in glioma cells. Further, Dual luciferase report assay was used to investigate the correlation between lnc-UCA1 and miR-627-5p. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate lnc-UCA1 and miR-627-5p function including cell proliferation, migration and invasion, and apoptosis, respectively. ChIP assays were used to ascertain the correlations between NR2C2 and SPOCK1 as well as NR2C2 between lnc-UCA1. This study confirmed that lnc-UCA1 was up-regulated in glioma tissues and cells. UCA1 knockdown inhibited the malignancies of glioma cells by reducing proliferation, migration, and invasion, but inducing apoptosis. We found that lnc-UCA1 acted as miR-627-5p sponge in a sequence-specific manner. Meanwhile, upregulated lnc-UCA1 inhibited miR-627-5p expression. In addition, miR-627-5p targeted 3'UTR of NR2C2 and down-regulated its expression. Moreover, UCA1 knockdown impaired NR2C2 expression by upregulating miR-627-5p. An uORF was identified in mRNA 5'UTR of NR2C2 and overexpression of whom negatively regulated NR2C2 expression. Remarkably, lnc-UCA1 knockdown combined with uORF overepression and NR2C2 knockdown led to severe tumor suppression in vivo. This study demonstrated that the NR2C2-uORF impaired the pivotal roles that UCA1-miR-627-5p-NR2C2 feedback loop had in regulating the malignancies of glioma cells by targeting NR2C2 directly. And this may provide a potential therapeutic strategy for treating glioma.

Dataset Information

FUS/circ_002136/miR-138-5p/SOX13 feedback loop regulates angiogenesis in Glioma.

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FUS/circ_002136/miR-138-5p/SOX13 feedback loop regulates angiogenesis in Glioma.

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