Long Noncoding RNA LPP-AS2 Promotes Glioma Tumorigenesis via miR-7-5p/EGFR/PI3K/AKT/c-MYC Feedback Loop

Abstract

Background: Glioma is the most common primary malignant intracranial tumor with poorly clinical prognosis in adults. Accumulating evidences indicate that long non-coding RNAs (lncRNAs) have served as important regulators in cancer progression, including glioma. Here, we identified a new lncRNA LPP antisense RNA-2 (LPP-AS2) and investigated its function and mechanism in the occurrence and development of glioma.Methods: High-throughput RNA sequencing was performed to discriminate the differentially expression lncRNAs and mRNAs between glioma tissues and normal brain tissues. The expression of LPP-AS2, epidermal growth factor receptor (EGFR) and miR-7-5p in glioma tissues and cell lines were detected by real-time quantitative PCR (RT-qPCR). The functions of lncRNA LPP-AS2 in glioma were measured by in vivo and in vitro assays. Insights of the underlying mechanism of competitive endogenous RNAs (ceRNAs) were originated from bioinformatic analysis, dual luciferase reporter assays, RNA pulldown assays, RNA immunoprecipitation (RIP) and rescue experiments. Results: The results of high-throughput RNA-seq indicated that lncRNA LPP-AS2 was upregulated in glioma tissues and further confirmed by RT-qPCR. Higher LPP-AS2 expression was related to poor prognosis of glioma patients. Functional studies illustrated that LPP-AS2 depletion inhibited glioma cell proliferation, invasion and promoted apoptosis in vitro and restrained tumor growth in vivo, whereas overexpression of LPP-AS2 resulted in opposite effects. In addition, LPP-AS2 and EGFR were observed of co-expression networks, and LPP-AS2 functioned as a ceRNA to regulate EGFR expression by sponging miR-7-5p in glioma cells. Result of chromatin immunoprecipitation (ChIP) assay validated that c-MYC was directly bind with promoter region of LPP-AS2. As a downstream protein of EGFR, c-MYC was modulated by LPP-AS2 and in turn increased LPP-AS2 expression. Thus, lncRNA LPP-AS2 promoted glioma tumorigenesis via a miR-7-5p/EGFR/PI3K/AKT/c-MYC feedback loop. Conclusions: Our study elucidated that LPP-AS2 acted as an oncogene through a novel molecular pathway in glioma and might be a potential therapeutic approach for glioma diagnosis, therapy and prognosis.