New insights into long noncoding RNAs and their roles in glioma

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Abstract

Glioma is one of the most prevalent types of primary intracranial carcinoma with varying malignancy grades I–IV and histological subtypes, including astrocytomas, glioblastoma multiform (GBM), oligodendrogliomas and mixed tumors. Glioma is characterized by rapid cell proliferation and angiogenesis, and the WHO grade IV glioblastoma, which is highly malignant with poor prognosis because GBM stem-like cells (GSCs) are resistant to conventional therapy and easily recrudescent, accounts for the majority of gliomas. Consequently, investigations exploring the accurate molecular mechanisms and reliable therapeutic targets for gliomas have drawn extensive attention.

Based on the increasing amount of functional lncRNAs aberrantly expressed in glioma tissues and cell lines, lncRNAs might be critical for glioma initiation, progression and other malignant phenotypes. This review summarizes the latest insights into the lncRNA field and their functional roles in glioma, therefore evaluating the potential clinical applications of lncRNAs as prospective novel biomarkers and therapeutic targets.

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MicroRNA silencing for cancer therapy targeted to the tumor microenvironment

Christopher J Cheng, Raman Bahal, Imran A Babar … (2015)

SUMMARY PARAGRAPH MicroRNAs (miRNAs) are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, miRNAs are critical cogs in numerous biological processes 1,2 , and dysregulated miRNA expression is correlated with many human diseases. Certain miRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumors that depend on these miRNAs are said to display oncomiR addiction 3–5 . Some of the most effective anticancer therapies target oncogenes like EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (i.e. antimiRs) is an evolving therapeutic strategy 6,7 . However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells 8 . Here we introduce a novel antimiR delivery platform that targets the acidic tumor microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We found that the attachment of peptide nucleic acid (PNA) antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produced a novel construct that could target the tumor microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumors (pH ~6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new paradigm in the use of antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.

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Long Noncoding RNANEAT1, Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/β-Catenin Pathway by Scaffolding EZH2.

Yunfei Wang, Qixue Wang, Jinquan Cai … (2018)

Purpose: Long noncoding RNAs have been implicated in gliomagenesis, but their mechanisms of action are mainly undocumented. Through public glioma mRNA expression data sets, we found thatNEAT1was a potential oncogene. We systematically analyzed the clinical significance and mechanism ofNEAT1in glioblastoma.Experimental Design:Initially, we evaluated whetherNEAT1expression levels could be regulated by EGFR pathway activity. We subsequently evaluated the effect ofNEAT1on the WNT/β-catenin pathway and its target binding gene. The animal model supported the experimental findings.Results:We found thatNEAT1levels were regulated by EGFR pathway activity, which was mediated by STAT3 and NFκB (p65) downstream of the EGFR pathway. Moreover, we found thatNEAT1was critical for glioma cell growth and invasion by increasing β-catenin nuclear transport and downregulating ICAT, GSK3B, and Axin2. Taken together, we found thatNEAT1could bind to EZH2 and mediate the trimethylation of H3K27 in their promoters.NEAT1depletion also inhibited GBM cell growth and invasion in the intracranial animal model.Conclusions:The EGFR/NEAT1/EZH2/β-catenin axis serves as a critical effector of tumorigenesis and progression, suggesting new therapeutic directions in glioblastoma.Clin Cancer Res; 24(3); 684-95. ©2017 AACR.

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Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment

Keisuke Katsushima, Atsushi Natsume, Fumiharu Ohka … (2016)

Targeting self-renewal is an important goal in cancer therapy and recent studies have focused on Notch signalling in the maintenance of stemness of glioma stem cells (GSCs). Understanding cancer-specific Notch regulation would improve specificity of targeting this pathway. In this study, we find that Notch1 activation in GSCs specifically induces expression of the lncRNA, TUG1. TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress differentiation genes by locus-specific methylation of histone H3K27 via YY1-binding activity in the nucleus. Furthermore, intravenous treatment with antisense oligonucleotides targeting TUG1 coupled with a drug delivery system induces GSC differentiation and efficiently represses GSC growth in vivo. Our results highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population.

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Author and article information

Contributors

Minghua Wu: 86-731-82355401 , wuminghua554@aliyun.com

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 19 February 2018

Publication date PMC-release: 19 February 2018

Publication date Collection: 2018

Volume: 17

Electronic Location Identifier: 61

Affiliations

[1 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Hunan Provincial Tumor Hospital and the Affiliated Tumor Hospital of Xiangya Medical School, , Central South University, ; Changsha, Hunan 410006 China

[2 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Cancer Research Institute, School of Basic Medical Science, , Central South University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Carcinogenesis, Ministry of Health, ; Changsha, Hunan 410078 China

Author information

Zixuan Peng http://orcid.org/0000-0003-3864-2765

Article

Publisher ID: 812

DOI: 10.1186/s12943-018-0812-2

PMC ID: 5817731

PubMed ID: 29458374

SO-VID: 73f5309d-740c-480b-ba48-069535ad3eca

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 15 September 2017

Date accepted : 8 February 2018

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: lncrnas,non-coding rna,glioma,biomarker,therapeutic targets

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: lncrnas, non-coding rna, glioma, biomarker, therapeutic targets

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New insights into long noncoding RNAs and their roles in glioma

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Most cited references 40

MicroRNA silencing for cancer therapy targeted to the tumor microenvironment

Long Noncoding RNANEAT1, Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/β-Catenin Pathway by Scaffolding EZH2.

Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment

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Cited by 195

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