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LncRNA MATN1-AS1 prevents glioblastoma cell from proliferation and invasion via RELA regulation and MAPK signaling pathway.

ABSTRACT: Background:Glioblastoma (GBM) is one of the most aggressive and malignant tumor types. Despite treatment advances, GBM pathogenesis still remains largely unknown. MATN1-AS1, an intron-retained long non-coding RNA (lncRNA), has been implicated in GBM development. However, the underlying mechanism has not been identified. This study aimed to examine MATN1-AS1 expression and uncover its role in GBM. Methods:LncRNAs with low expression levels were selected by analyzing brain glioma-related genes. The relative mRNA level of MATN1-AS1 was quantified using RT-qPCR in 75 GBM tumors and 10 normal brain tissues. Overall survival was assessed using the Kaplan-Meier method. RT-qPCR and immunoblotting analysis were carried out to assess the levels of MATN1-AS1, RELA, ERK1/2, Bcl-2, Bax, survivin, and MMP-9 in GBM cells. Biological functions of MATN1-AS1 in GBM tumors were measured both in vivo and in vitro. The mechanism of RELA regulation by MATN1-AS1 was detected using RNA pull-down, RNA-binding protein immunoprecipitation, chromatin immunoprecipitation, and the dual luciferase reporter gene assay. Results:MATN1-AS1 was the most downregulated lncRNA in GBM and was correlated with a shorter survival time and poorer prognosis of GBM patients. Conversely, RELA was increased in GBM tumor tissues and negatively correlated with MATN1-AS1 expression. MATN1-AS1 over-expression or siRNA-RELA knockdown resulted in downregulation of mRNA and protein levels of RELA, ERK1/2, Bcl-2, survivin, and MMP-9; reduced cell proliferation and invasion; increased Bax mRNA and protein levels; and enhanced cellular apoptosis. MATN1-AS1 bound to E2F6, which negatively targeted RELA. Furthermore, MATN1-AS1 over-expression in GBM cells resulted in significant inhibition of tumor growth in vivo. Conclusions:Upregulation of the lncRNA MATN1-AS1 inhibited GBM cell proliferation and invasion through inhibition of RELA via E2F6 and suppression of the MAPK signaling pathway. MATN1-AS1 might be an underlying therapeutic target for GBM.

SUBMITTER: Han N

PROVIDER: S-EPMC6990012 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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LncRNA MATN1-AS1 prevents glioblastoma cell from proliferation and invasion via RELA regulation and MAPK signaling pathway.

Han Na N Yang Li L Zhang Xiaoxi X Zhou Yangmei Y Chen Rui R Yu Yang Y Dong Zhen Z Zhang Mengxian M

Annals of translational medicine 20191201 23

<h4>Background</h4>Glioblastoma (GBM) is one of the most aggressive and malignant tumor types. Despite treatment advances, GBM pathogenesis still remains largely unknown. MATN1-AS1, an intron-retained long non-coding RNA (lncRNA), has been implicated in GBM development. However, the underlying mechanism has not been identified. This study aimed to examine MATN1-AS1 expression and uncover its role in GBM.<h4>Methods</h4>LncRNAs with low expression levels were selected by analyzing brain glioma-re ...[more]

PMID: 32042800

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Project description:GBM (Glioblastoma multiform) is the most malignant tumor type of the central nervous system and has poor diagnostic and clinical outcomes. LncRNAs (Long non-coding RNAs) have been reported to participate in multiple biological and pathological processes, but their underlying mechanism remains poorly understood. Here, we aimed to explore the role of the lncRNA HAS2-AS1 (HAS2 antisense RNA 1) in GBM. GSE103227 was analyzed, and qRT-PCR was performed to measure the expression of HAS2-AS1 in GBM. FISH (Fluorescence in situ hybridization) was performed to verify the localization of HAS2-AS1. The interaction between HAS2-AS1 and miR-137 (microRNA-137) was predicted by LncBook and miRcode followed by dual-luciferase reporter assays, and the relationships among HAS2-AS1, miR-137 and LSD1 (lysine-specific demethylase 1) were assessed by WB (western blot) and qRT-PCR. Colony formation and CCK-8 (cell counting kit-8) assays were performed as functional tests. In vivo, nude mice were used to confirm the function of HAS2-AS1. HAS2-AS1 expression was upregulated in GBM cell lines, and HAS2-AS1 was localized mainly in the cytoplasm. In vitro, high HAS2-AS1 expression promoted proliferation, and knockdown of HAS2-AS1 significantly inhibited proliferation. Furthermore, HAS2-AS1 functioned as a ceRNA (competing endogenous RNA) of miR-137, leading to the disinhibition of its downstream target LSD1. The miR-137 level was downregulated by HAS2-AS1 overexpression and upregulated by HAS2-AS1 knockdown. In a subsequent study, LSD1 expression was negatively regulated by miR-137, while miR-137 reversed the LSD1 expression levels caused by HAS2-AS1. These results were further supported by the nude mouse tumorigenesis experiment; compared with xenografts with high HAS2-AS1 expression, the group with low levels of HAS2-AS1 exhibited suppressed proliferation and better survival. We conclude that lncRNA HAS2-AS1 promotes proliferation by functioning as a miR-137 decoy to increase LSD1 levels and thus might be a possible biomarker for GBM.

Dataset Information

LncRNA MATN1-AS1 prevents glioblastoma cell from proliferation and invasion via RELA regulation and MAPK signaling pathway.

Publications

LncRNA MATN1-AS1 prevents glioblastoma cell from proliferation and invasion via RELA regulation and MAPK signaling pathway.

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