Long Non-Coding RNA HOXA-AS2 Regulates Malignant Glioma Behaviors and Vasculogenic Mimicry Formation via the MiR-373/EGFR Axis

• Published in: Cellular physiology and biochemistry Vol. 45; no. 1; pp. 131 - 147
• Main Authors: Gao, Yana, Yu, Hai, Liu, Yunhui, Liu, Xiaobai, Zheng, Jian, Ma, Jun, Gong, Wei, Chen, Jiajia, Zhao, Lini, Tian, Yu, Xue, Yixue
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2018; Cell Physiol Biochem Press GmbH & Co KG
• Subjects: Animals; Biotechnology; Brain - metabolism; Brain - pathology; Brain Neoplasms - blood supply; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Breast cancer; Cell adhesion & migration; Cell growth; Cell Line, Tumor; Cell Movement; Cell Proliferation; EGFR; Epidermal growth factor; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gene expression; Glioma; Glioma - blood supply; Glioma - metabolism; Glioma - pathology; HOXA-AS2; Humans; Kinases; Long non-coding RNA; Male; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; MiR-373; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases - metabolism; Prostate cancer; Retracted Paper; RNA Interference; RNA, Long Noncoding - antagonists & inhibitors; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Up-Regulation; Vasculogenic mimicry; United States > US; China; Japan; MicroRNA; Glioma; HOXA-AS2; MiR-373; EGFR; Long non-coding RNA; Vasculogenic mimicry
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000486253

Vasculogenic mimicry (VM) has been reported to be a novel glioma neovascularization process. Anti-VM therapy provides new insight into glioma clinical management. In this study, we revealed the role of the long non-coding RNA HOXA cluster antisense RNA 2 (HOXA-AS2) in malignant glioma behaviors and VM formation. Quantitative real-time PCR was performed to determine the expression levels of HOXA-AS2 in glioma samples and glioblastoma cell lines. CD34-periodic acid-Schiff dual-staining was performed to assess VM in glioma samples. CCK-8, transwell, and Matrigel tube formation assays were performed to measure the effects of HOXA-AS2 knockdown on cell viability, migration, invasion, and VM tube formation, respectively. RNA immunoprecipitation, dual-luciferase reporter and Western blot assays were performed to explore the molecular mechanisms underlying the functions of HOXS-AS2 in glioblastoma cells. A nude mouse xenograft model was used to investigate the role of HOXA-AS2 in xenograft glioma growth and VM density. Student's t-tests, one-way ANOVAs followed by Bonferroni posthoc tests, and chi-square tests were used for the statistical analyses. HOXA-AS2 was upregulated in glioma samples and cell lines and was positively correlated with VM. HOXA-AS2 knockdown attenuated cell viability, migration, invasion, and VM formation in glioma cells and inhibited the expression of vascular endothelial-cadherin (VE-cadherin), as well as the expression and activity of matrix metalloproteinase matrix metalloproteinase (MMP)-2 and MMP-9. miR-373 was downregulated in glioma samples and cell lines and suppressed malignancy in glioblastoma cells. HOXA-AS2 bound to miR-373 and negatively regulated its expression. Epidermal growth factor receptor (EGFR), a target of miR-373, increased the expression levels of VE-cadherin, as well as the expression and activity levels of MMP-2 and MMP-9, via activating phosphatidylinositol 3-kinase/serine/threonine kinase pathways. HOXA-AS2 knockdown combined with miR-373 overexpression yielded optimal tumor suppressive effects and the lowest VM density in vivo. HOXA-AS2 knockdown inhibited malignant glioma behaviors and VM formation via the miR-373/EGFR axis.