Abstract
Gliomas are characterized by high incidence, recurrence and mortality all of which are significant challenges to efficacious clinical treatment. The hypoxic microenvironment in the inner core and intermediate layer of the tumor mass of gliomas is a critical contributor to glioma pathogenesis. In this study, we identified an upregulated lncRNA, OR7E156P, in glioma was identified. The silencing of OR7E156P inhibited cell invasion and DNA synthesis in vitro and tumor growth in vivo. OR7E156P was intricately linked to the HIF1A pathway. Hypoxia could induce OR7E156P expression, whereas OR7E156P silencing decreased HIF1A protein levels under hypoxic conditions. Hypoxia promoted glioma cell invasion and DNA synthesis, and HUVEC tube formation, whereas OR7E156P silencing partially reversed the cellular effects of hypoxia. HIF1A overexpression promoted, whereas OR7E156P silencing inhibited tumor growth; the inhibitory effects of OR7E156P silencing on tumor growth were partially reversed by HIF1A overexpression. miR-143 directly targeted OR7E156P and HIF1A, respectively. miR-143 inhibition increased HIF1A protein levels, promoted glioma cell invasion and DNA synthesis. Moreover, they enhanced HUVEC tube formation, whereas OR7E156P silencing partially reversed the cellular effects of miR-143 inhibition. HIF1A targeted the promoter region of miR-143 and inhibited miR-143 expression. Altogether a regulatory axis consisting of OR7E156P, miR-143, and HIF1A, was identified which is deregulated in glioma, and the process of the OR7E156P/miR-143/HIF1A axis modulating glioma cell invasion through ZEB1 and HUVEC tube formation through VEGF was demonstrated.
Highlights
Gliomas are the most common cerebral malignancies [1]
Two online datasets were selected and analyzed, the TCGAGBM microarray dataset (AffyU133a) from Xena and the GSE42658, to identify long noncoding RNA (lncRNA) related to glioma carcinogenesis using bioinformatics analysis
The expression of CYB561D2, DLEU1, HCP5 and OR7E156P were examined in a human fetal glial cell line, SVG p12, and four glioma cell lines, U87-MG, T98-G, U251MGU251-MG MG, and LN229; Figure 1B reveals that the expression of all the four lncRNAs was significantly upregulated in all the four glioma cell lines compared with that in the SVG p12 cell line; among the four lncRNAs, OR7E156P was more upregulated
Summary
Gliomas are the most common cerebral malignancies [1]. Gliomas are characterized by high incidence, recurrence and fatality, with poor prognosis [2,3,4]. The main research direction is to identify agents inhibiting the invasion and growth of gliomas to improve the current treatment regimens. The oncogenic role of short ncRNAs such as miRNAs have been a long-lasting research topic [6]. The mutual regulation between lncRNA and miRNA has been reported in tumors [13,14,15]. Regarding gliomas, it has been revealed by Jia et al [16] that lncRNA-H19 can regulate glioma angiogenesis and endothelial biological function through the inhibition of miR-29a. Ke et al [17] reported that lncRNA HOTAIR interacts with miR326 to regulate glioma cell proliferation and invasion. With the advent of the high-throughput sequencing technique, the identification of deregulated non-coding RNA network in glioma could potentially provide novel targets for glioma therapy
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