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      Clinicopathological significance and a potential drugtarget of RARβ in non-small-cell lung carcinoma: a meta-analysis and a systematic review

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          Abstract

          Lung cancer is the leading cause of cancer-related mortality in men worldwide. Aberrant RARβ promoter methylation has been frequently investigated in non-small-cell lung carcinoma (NSCLC), the most common form of lung cancer. The aim of present study was to carry out a meta-analysis and a systematic review to evaluate clinicopathological significance of RARβ promoter hypermethylation in NSCLC. A systematic literature search was carried out. The data were extracted and assessed by two reviewers independently. The Cochrane software Review Manager 5.2 was used to conduct the review. Odds ratios (ORs) with 95% corresponding confidence intervals (CIs) were calculated. A total of 18 relevant articles were available for meta-analysis which included 1,871 participants. The frequency of RARβ hypermethylation was significantly increased in NSCLC than in nonmalignant lung tissue, and the pooled OR was 5.69 ( P<0.00001). RARβ hypermethylation was significantly more frequently observed in adenocarcinoma (AC) than in squamous cell carcinoma (SCC), and the pooled OR was 1.47 ( P=0.005). Hypermethylation of RARβ gene in NSCLC was 2.46 times higher in smoking than in nonsmoking individuals, and the pooled OR was 2.46 ( P=0.0002). RARβ hypermethylation rate was not significantly correlated with stage of the disease and sex. RARβ gene methylation status was not associated with prognosis of patients with NSCLC. In conclusion, RARβ promoter hypermethylation significantly increased in NSCLC than in non-neoplastic lung tissue and is predominant in AC, suggesting that RARβ methylation contributes to the development of NSCLC, especially AC. RARβ gene is a potential novel target for development of personalized therapy in patients with NSCLC, and is promising in restoration of retinoic acid-target gene induction via demethylation of RARβ1′ promoter.

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          Most cited references 47

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          Tobacco smoke and involuntary smoking.

            (2003)
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            Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer.

            Gene function in cancer can be disrupted either through genetic alterations, which directly mutate or delete genes, or epigenetic alterations, which alter the heritable state of gene expression. The latter events are mediated by formation of transcriptionally repressive chromatin states around gene transcription start sites and an associated gain of methylation in normally unmethylated CpG islands in these regions. The genes affected include over half of the tumor suppressor genes that cause familial cancers when mutated in the germline; the selective advantage for genetic and epigenetic dysfunction in these genes is very similar. The aberrant methylation can begin very early in tumor progression and mediate most of the important pathway abnormalities in cancer including loss of cell cycle control, altered function of transcription factors, altered receptor function, disruption of normal cell-cell and cell-substratum interaction, inactivation of signal transduction pathways, loss of apoptotic signals and genetic instability. The active role of the aberrant methylation in transcriptional silencing of genes is becoming increasingly understood and involves a synergy between the methylation and histone deacetylase (HDAC) activity. This synergy can be mediated directly by HDAC interaction with DNA methylating enzymes and by recruitment through complexes involving methyl-cytosine binding proteins. In the translational arena, the promoter hypermethylation changes hold great promise as DNA tumor markers and their potentially reversible state creates a target for cancer therapeutic strategies involving gene reactivation.
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              5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers.

              Loss of heterozygosity on chromosome 9p21 is one of the most frequent genetic alterations identified in human cancer. The rate of point mutations of p16, a candidate suppressor gene of this area, is low in most primary tumours with allelic loss of 9p21. Monosomic cell lines with structurally unaltered p16 show methylation of the 5' CpG island of p16. This distinct methylation pattern was associated with a complete transcriptional block that was reversible upon treatment with 5-deoxyazacytidine. Moreover, de novo methylation of the 5' CpG island of p16 was also found in approximately 20% of different primary neoplasms, but not in normal tissues, potentially representing a common pathway of tumour suppressor gene inactivation in human cancers.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                06 April 2016
                : 10
                : 1345-1354
                Affiliations
                Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China
                Author notes
                Correspondence: Zhidong Liu; Yi Han, Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, No 97, Machang, Tongzhou District, Beijing 101149, People’s Republic of China, Email zhidongliu66@ 123456yahoo.com ; hanyi588@ 123456yahoo.com
                [*]

                These authors contributed equally to this work

                Article
                dddt-10-1345
                10.2147/DDDT.S96766
                4827914
                27103788
                © 2016 Song et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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