Abstract
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.
Highlights
Glioblastoma multiform is the most common primary carcinoma in adults, and standard treatments include tumor excision, radiotherapy and chemotherapy; the clinical outcomes of patients remain poor
Zhuoran Zhang et al found that the lncRNA SBF2-AS1 enhances temozolomide resistance in GBM [19], and HAS2-AS1, which is located at the 8q24.13 locus, was reported to be an oncogene in oral squamous cell carcinoma [20]
The level of HAS2-AS1 was positively correlated with the WHO grade of glioma (Figure 1A), which indicated that HAS2-AS1 may be involved in the tumorigenesis processes in GBM
Summary
Glioblastoma multiform is the most common primary carcinoma in adults, and standard treatments include tumor excision, radiotherapy and chemotherapy; the clinical outcomes of patients remain poor. The median survival time of patients is only 14 months, with a 5.5% five-year survival rate [1, 2]. Numerous obstacles, such as the blood-brain barrier [3, 4], high tumor invasiveness [5], tumor heterogeneity [6], and temozolomide resistance [7], impede the effectiveness of GBM treatment. Aberrant lncRNA levels play vital roles in tumorigenic processes, such as tumor initiation and progression, chromosome instability, promotion of cell proliferation, resistance to apoptosis, and cancer metastasis [16,17,18]. We found that HAS2-AS1 promotes cell proliferation by sponging miR-137 to regulate LSD1 expression, which may provide a novel molecular mechanism of GBM
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