Long Noncoding RNA HOTAIRM1 Maintains Tumorigenicity of Glioblastoma Stem-Like Cells Through Regulation of HOX Gene Expr
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ORIGINAL ARTICLE
Long Noncoding RNA HOTAIRM1 Maintains Tumorigenicity of Glioblastoma Stem-Like Cells Through Regulation of HOX Gene Expression Hongping Xia 1,2,3
&
Yinhua Liu 4 & Zhichun Wang 1 & Wei Zhang 4 & Min Qi 1 & Bin Qi 5 & Xiaochun Jiang 1
# The American Society for Experimental NeuroTherapeutics, Inc. 2019
Abstract Noncoding RNAs regulate transcription of gene expression and play an important role in the pathogenesis of glioblastomas. These tumors are heterogeneous with some glioma stem cells (GSCs) that are highly tumorigenic subpopulations of cells contributing to recurrence and treatment resistance. In this study, GSCs were established by neurosphere cultures of primary glioblastoma cells and validated by the expression of GSC marker CD133. The expression of the long noncoding RNA HOTAIRM1 was detected using real-time quantitative reverse transcription PCR (qRT-PCR). The role of HOTAIRM1 in the proliferation, apoptosis, stemness, and tumorigenicity of GSCs was investigated by soft agar colony formation, flow cytometry, TUNEL analysis, sphere formation, and in vivo xenograft models through silencing of HOTAIRM1. The expression of HOTAIRM1 and the neighboring HOX genes were analyzed by qRT-PCR in different grades of gliomas and nontumor tissues. We found that HOTAIRM1 is significantly elevated in GSCs. The silencing of HOTAIRM1 significantly impairs the proliferation, apoptosis, self-renewal, tumorigenesis of GSCs. In addition, HOTAIRM1 is significantly upregulated in gliomas and associated with tumor grade and patient survival. HOTAIRM1 neighboring genes, HOXA1, HOXA2, and HOXA3, are also significantly upregulated in gliomas and correlate with the expression of HOTAIRM1. Among them, HOXA2 and HOXA3 were identified as being upregulated in GSCs and contributed to the self-renewal of these stem cells. Taken together, our results demonstrate that HOTAIRM1 plays a critical role in the self-renewal of GSCs. These data also suggest that overexpression of HOTAIRM1 can be a negative prognostic factor for patient survival in malignant glioma and may be a promising potential therapeutic target. Key Words Glioblastoma stem cells . CD133 . LncRNAs . HOTAIRM1 . HOX genes
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13311-019-00799-0) contains supplementary material, which is available to authorized users. * Hongping Xia [email protected] * Xiaochun Jiang [email protected] 1
2
Department of Neurosurgery, Yijishan Hospital, Wannan Medical College, Wuhu 241001, China Department of Pathology, School of Basic Medical Sciences & The Affiliated Sir Run Run Hospital & State Key Laboratory of Reproductive Medicine & Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China
3
Department of Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
4
Department of Pathology, Yijishan Hospital, Wannan Medical College, Wuhu 241001, China
5
Department of Neurosu
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