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Inhibition of TDP43-Mediated SNHG12-miR-195-SOX5 Feedback Loop Impeded Malignant Biological Behaviors of Glioma Cells.

ABSTRACT: Long non-coding RNA (lncRNA) dysregulation is involved in tumorigenesis and regulation of diverse cellular processes in gliomas. lncRNA SNHG12 is upregulated and promotes cell growth in human osteosarcoma cells. TAR-DNA binding protein 43 (TDP43) functions as an oncogene in various tumors by modulating RNA expression. Downregulation of TDP43 or SNHG12 significantly inhibited malignant biological behaviors of glioma cells. miR-195, downregulated in glioma tissues and cells, significantly impaired the malignant progression of glioma cells. TDP43 upregulated miR-195 in an SNHG12-dependent manner. We further revealed that SNHG12 and miR-195 were in an RNA-induced silencing complex (RISC). Inhibition of SNHG12 combined with restoration of miR-195 robustly reduced tumor growth in vivo. SOX5 was overexpressed in glioma tissues and cells. miR-195 targeted SOX5 3' UTR in a sequence-specific manner. Gelsolin was activated by SOX5. More importantly, SOX5 activated SNHG12 promoter and upregulated its expression, forming a feedback loop. Dysregulation of SNHG12, miR-195, and SOX5 predicted poor prognosis of glioma patients. The present study demonstrated that SNHG12-miR-195-SOX5 feedback loop exerted a crucial role in the regulation of glioma cells' malignant progression.

SUBMITTER: Liu X

PROVIDER: S-EPMC5751968 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Inhibition of TDP43-Mediated SNHG12-miR-195-SOX5 Feedback Loop Impeded Malignant Biological Behaviors of Glioma Cells.

Liu Xiaobai X Zheng Jian J Xue Yixue Y Qu Chengbin C Chen Jiajia J Wang Zhenhua Z Li Zhen Z Zhang Lei L Liu Yunhui Y

Molecular therapy. Nucleic acids 20171208

Long non-coding RNA (lncRNA) dysregulation is involved in tumorigenesis and regulation of diverse cellular processes in gliomas. lncRNA SNHG12 is upregulated and promotes cell growth in human osteosarcoma cells. TAR-DNA binding protein 43 (TDP43) functions as an oncogene in various tumors by modulating RNA expression. Downregulation of TDP43 or SNHG12 significantly inhibited malignant biological behaviors of glioma cells. miR-195, downregulated in glioma tissues and cells, significantly impaired ...[more]

PMID: 29499929

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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.

Project description:BackgroundGlioma is the most common and lethal type of malignant brain tumor. Accumulating evidence has highlighted that RNA binding protein APOBEC1 complementation factor (A1CF) is involved in various cellular processes by modulating RNA expression, and acts as an oncogene in breast cancer. However, the function of A1CF in glioma remained unclear.MethodsQuantitative RT-PCR and western blot analysis were employed to detect the expression levels of A1CF, lncRNA family with sequence similarity 224 member A (FAM224A), miR-590-3p, zinc finger protein 143 (ZNF143) and ArfGAP with SH3 domain, ankyrin repeat and PH domain 3 (ASAP3) in glioma tissues and cell lines. The Cell Counting Kit-8 assay, migration and invasion assays, and flow cytometry analysis were conducted to evaluate the function of A1CF, FAM224A, miR-590-3p, ZNF143 and ASAP3 in the malignant biological behaviors of glioma cells. Moreover, luciferase reporter, RIP and ChIP assays were used to investigate the interactions among A1CF, FAM224A, miR-590-3p, ZNF143, ASAP3 and MYB. Finally, the xenograft tumor growth assay further ascertained the biological roles of A1CF, FAM224A and miR-590-3p in glioma cells.ResultsA1CF was upregulated and functioned as an oncogene via stabilizing and increasing FAM224A expression; moreover, high A1CF and FAM224A expression levels indicated a poorer prognosis for glioma patients. Conversely, miR-590-3p was downregulated and exerted a tumor-suppressive function in glioma cells. Inhibition of A1CF significantly restrained cell proliferation, migration and invasion, and promoted apoptosis by upregulating miR-590-3p in a FAM224A-dependent manner. FAM224A was a molecular sponge of miR-590-3p and they were in an RNA-induced silencing complex. ZNF143 was upregulated in glioma tissues and cell lines. MiR-590-3p could negatively modulate the expression of ZNF143 via binding to the ZNF143 3' UTR. Moreover, ZNF143 participated in miR-590-3p-induced tumor-suppressive activity on glioma cells. ASAP3 and MYB were transcriptionally activated by ZNF143, and importantly, ZNF143 could directly target the promoter of FAM224A and stimulate its expression, collectively forming a positive feedback loop.ConclusionsThe present study clarifies that the A1CF-FAM224A-miR-590-3p-ZNF143 positive feedback loop conducts critical regulatory effects on the malignant progression of glioma cells, which provides a novel molecular target for glioma therapy.

Project description:BackgroundAngiogenesis 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.MethodsThe 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 .ResultsWe 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.ConclusionOur 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.

Dataset Information

Inhibition of TDP43-Mediated SNHG12-miR-195-SOX5 Feedback Loop Impeded Malignant Biological Behaviors of Glioma Cells.

Publications

Inhibition of TDP43-Mediated SNHG12-miR-195-SOX5 Feedback Loop Impeded Malignant Biological Behaviors of Glioma Cells.

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