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      Low GAS5 Levels as a Predictor of Poor Survival in Patients with Lower-Grade Gliomas

      research-article
      1 , 1 , 2 , 1 , , 3 , 4 ,
      Journal of Oncology
      Hindawi

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          Abstract

          Introduction

          Gliomas are infiltrative neoplasms of a highly invasive nature. Different stages of gliomas feature distinct genomic, genetic, and epigenetic changes. The long noncoding RNA Growth Arrest Specific Transcript 5 (GAS5) is an identified tumour suppressor involved in several cancers. However, the underlying roles of the GAS5 gene in lower-grade glioma (LGG) patients are not clear.

          Methods

          Via bioinformatic analysis based on TCGA-LGG and TCGA-GBM data, we explored the mechanisms of GAS5 expression in LGG (grades II and III) and high-grade glioma (glioblastoma multiforme, grade IV). The log-rank test and multivariate Cox analysis were performed to find the association between GAS5 and overall survival (OS) in LGG patients. Weighted gene coexpression network analysis (WGCNA) and RNA-Seq analysis were applied to find the key gene network associated with GAS5.

          Results

          We found that GAS5 expression was downregulated in both LGG and glioblastoma multiforme (GBM) compared with normal brain tissue. Low methylation in the GAS5 promoter region was detected in both LGG and GBM tissues. The amplification type was the predominant type of GAS5 gene alteration in both LGG and GBM. High GAS5 expression was more associated with long overall survival (OS) in LGG patients than in GBM patients. The multivariate survival analysis of GAS5 and clinical and molecular characteristics in LGG patients further confirmed the association between GAS5 and OS in LGG patients. We then developed a nomogram for clinical use. WGCNA and RNA-Seq analysis indicated that ribosomal biogenesis and translation initiation were the predominant events regulated by GAS5 in LGG patients.

          Conclusion

          Taken together, these results demonstrate that GAS5 expression is associated with OS in LGG patients and that its underlying roles involve the regulation of ribosomal biogenesis and translation initiation, which may aid in identifying a new target for the treatment of LGG.

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          Most cited references18

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          A long noncoding RNA mediates both activation and repression of immune response genes.

          An inducible program of inflammatory gene expression is central to antimicrobial defenses. This response is controlled by a collaboration involving signal-dependent activation of transcription factors, transcriptional co-regulators, and chromatin-modifying factors. We have identified a long noncoding RNA (lncRNA) that acts as a key regulator of this inflammatory response. Pattern recognition receptors such as the Toll-like receptors induce the expression of numerous lncRNAs. One of these, lincRNA-Cox2, mediates both the activation and repression of distinct classes of immune genes. Transcriptional repression of target genes is dependent on interactions of lincRNA-Cox2 with heterogeneous nuclear ribonucleoprotein A/B and A2/B1. Collectively, these studies unveil a central role of lincRNA-Cox2 as a broad-acting regulatory component of the circuit that controls the inflammatory response.
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            GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer.

            Effective control of both cell survival and cell proliferation is critical to the prevention of oncogenesis and to successful cancer therapy. Using functional expression cloning, we have identified GAS5 (growth arrest-specific transcript 5) as critical to the control of mammalian apoptosis and cell population growth. GAS5 transcripts are subject to complex post-transcriptional processing and some, but not all, GAS5 transcripts sensitize mammalian cells to apoptosis inducers. We have found that, in some cell lines, GAS5 expression induces growth arrest and apoptosis independently of other stimuli. GAS5 transcript levels were significantly reduced in breast cancer samples relative to adjacent unaffected normal breast epithelial tissues. The GAS5 gene has no significant protein-coding potential but expression encodes small nucleolar RNAs (snoRNAs) in its introns. Taken together with the recent demonstration of tumor suppressor characteristics in the related snoRNA U50, our observations suggest that such snoRNAs form a novel family of genes controlling oncogenesis and sensitivity to therapy in cancer.
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              Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas.

              There are no controlled studies on surgical treatment of diffuse low-grade gliomas (LGGs), and management is controversial. To examine survival in population-based parallel cohorts of LGGs from 2 Norwegian university hospitals with different surgical treatment strategies. Both neurosurgical departments are exclusive providers in adjacent geographical regions with regional referral practices. In hospital A diagnostic biopsies followed by a "wait and scan" approach has been favored (biopsy and watchful waiting), while early resections have been advocated in hospital B (early resection). Thus, the treatment strategy in individual patients has been highly dependent on the patient's residential address. Histopathology specimens from all adult patients diagnosed with LGG from 1998 through 2009 underwent a blinded histopathological review to ensure uniform classification and inclusion. Follow-up ended April 11, 2011. There were 153 patients (66 from the center favoring biopsy and watchful waiting and 87 from the center favoring early resection) with diffuse LGGs included. The prespecified primary end point was overall survival based on regional comparisons without adjusting for administered treatment. Results Initial biopsy alone was carried out in 47 (71%) patients served by the center favoring biopsy and watchful waiting and in 12 (14%) patients served by the center favoring early resection (P < .001). Median follow-up was 7.0 years (interquartile range, 4.5-10.9) at the center favoring biopsy and watchful waiting and 7.1 years (interquartile range, 4.2-9.9) at the center favoring early resection (P=.95). The 2 groups were comparable with respect to baseline parameters. Overall survival was significantly better with early surgical resection (P=.01). Median survival was 5.9 years (95% CI, 4.5-7.3) with the approach favoring biopsy only while median survival was not reached with the approach favoring early resection. Estimated 5-year survival was 60% (95% CI, 48%-72%) and 74% (95% CI, 64%-84%) for biopsy and watchful waiting and early resection, respectively. In an adjusted multivariable analysis the relative hazard ratio was 1.8 (95% CI, 1.1-2.9, P=.03) when treated at the center favoring biopsy and watchful waiting. For patients in Norway with LGG, treatment at a center that favored early surgical resection was associated with better overall survival than treatment at a center that favored biopsy and watchful waiting. This survival benefit remained after adjusting for validated prognostic factors.
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                Author and article information

                Contributors
                Journal
                J Oncol
                J Oncol
                JO
                Journal of Oncology
                Hindawi
                1687-8450
                1687-8469
                2019
                3 February 2019
                : 2019
                : 1785042
                Affiliations
                1Ludwig-Maximilians-Universität München (LMU), 80539 Munich, Germany
                2Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310016 Hangzhou, China
                3Institute of Radiation Biology, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany
                4Technical University Munich (TUM), 80333 Munich, Germany
                Author notes

                Academic Editor: Srikumar P. Chellappan

                Author information
                http://orcid.org/0000-0002-8256-1180
                http://orcid.org/0000-0003-4667-4812
                http://orcid.org/0000-0002-6232-3783
                Article
                10.1155/2019/1785042
                6377997
                3a83393c-aed7-452e-bd68-5b332c82bd0e
                Copyright © 2019 Yanfang Wang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 1 October 2018
                : 18 December 2018
                : 3 January 2019
                Categories
                Research Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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