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      Long non‐coding RNA linc01433 promotes migration and invasion in non‐small cell lung cancer

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          Abstract

          Background

          For many years, lung cancer has been the most common and deadly cancer worldwide. Early diagnosis of non‐small cell lung cancer (NSCLC) in particular is very difficult because the symptoms are often ignored. The five‐year survival rate is very low despite great improvements to therapy. Thus, there is an urgent need to identify prognostic biomarkers and target molecules for the clinical diagnosis and individualized treatment of NSCLC.

          Methods

          We performed quantitative real‐time PCR to determine the expression levels of the long non‐coding RNA (lncRNA) linc01433 in NSCLC and normal matched lung tissue. Subsequently, we established cell lines with overexpression or knockdown of linc01433 to evaluate the effects on proliferation and metastasis in vitro. Epithelial‐to‐mesenchymal transition was examined using Western blot.

          Results

          Linc01433 was significantly overexpressed in NSCLC tissues compared to normal lung tissues. In addition, linc01433 levels were associated with smoking history. Linc01433 overexpression in lung cancer cells increased proliferation, migration, and invasion abilities, as well as epithelial‐to‐mesenchymal transition.

          Conclusions

          Linc01433 is a cancer‐related lncRNA that may have an oncogene‐like effect in NSCLC.

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          Most cited references26

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          P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression

          Recently, a novel class of transcripts, long non-coding RNAs (lncRNAs), is being identified at a rapid pace. These RNAs have critical roles in diverse biological processes, including tumorigenesis. Here we report that taurine-upregulated gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is generally downregulated in non-small cell lung carcinoma (NSCLC) tissues. In a cohort of 192 NSCLC patients, the lower expression of TUG1 was associated with a higher TNM stage and tumor size, as well as poorer overall survival (P<0.001). Univariate and multivariate analyses revealed that TUG1 expression serves as an independent predictor for overall survival (P<0.001). Further experiments revealed that TUG1 expression was induced by p53, and luciferase and chromatin immunoprecipitation (ChIP) assays confirmed that TUG1 was a direct transcriptional target of p53. TUG1 knockdown significantly promoted the proliferation in vitro and in vivo. Moreover, the lncRNA-mediated regulation of the expression of HOX genes in tumorigenesis and development has been recently receiving increased attention. Interestingly, inhibition of TUG1 could upregulate homeobox B7 (HOXB7) expression; ChIP assays demonstrated that the promoter of HOXB7 locus was bound by EZH2 (enhancer of zeste homolog 2), a key component of PRC2, and was H3K27 trimethylated. This TUG1-mediated growth regulation is in part due to specific modulation of HOXB7, thus participating in AKT and MAPK pathways. Together, these results suggest that p53-regulated TUG1 is a growth regulator, which acts in part through control of HOXB7. The p53/TUG1/PRC2/HOXB7 interaction might serve as targets for NSCLC diagnosis and therapy.
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            FOXP3 promotes tumor growth and metastasis by activating Wnt/β-catenin signaling pathway and EMT in non-small cell lung cancer

            Background The role of cancer cell FOXP3 in tumorigenesis is conflicting. We aimed to study FOXP3 expression and regulation, function and clinical implication in human non-small cell lung cancer (NSCLC). Methods One hundred and six patients with histologically-confirmed NSCLC who underwent surgery were recruited for the study. Tumor samples and NSCLC cell lines were used to examine FOXP3 and its related molecules. Various cell functions related to tumorigenesis were performed. In vivo mouse tumor xenograft was used to confirm the in vitro results. Results NSCLC patients with the high level of FOXP3 had a significant decrease in overall survival and recurrence-free survival. FOXP3 overexpression significantly induced cell proliferation, migration, and invasion, whereas its inhibition impaired its oncogenic function. In vivo studies confirmed that FOXP3 promoted tumor growth and metastasis. The ectopic expression of FOXP3 induced epithelial–mesenchymal transition (EMT) with downregulation of E-cadherin and upregulation of N-cadherin, vimentin, snail, slug, and MMP9. The oncogenic effects by FOXP3 could be attributed to FOX3-mediated activation of Wnt/β-catenin signaling, as FOXP3 increased luciferase activity of Topflash reporter and upregulated Wnt signaling target genes including c-Myc and Cyclin D1 in NSCLC cells. Co-immunoprecipitation results further indicated that FOXP3 could physically interacted with β-catenin and TCF4 to enhance the functions of β-catenin and TCF4, inducing transcription of Wnt target genes to promote cell proliferation, invasion and EMT induction. Conclusions FOXP3 can act as a co-activator to facilitate the Wnt-b-catenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0700-1) contains supplementary material, which is available to authorized users.
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              ZEB1 drives epithelial-to-mesenchymal transition in lung cancer.

              Increased expression of zinc finger E-box binding homeobox 1 (ZEB1) is associated with tumor grade and metastasis in lung cancer, likely due to its role as a transcription factor in epithelial-to-mesenchymal transition (EMT). Here, we modeled malignant transformation in human bronchial epithelial cells (HBECs) and determined that EMT and ZEB1 expression are early, critical events in lung cancer pathogenesis. Specific oncogenic mutations in TP53 and KRAS were required for HBECs to engage EMT machinery in response to microenvironmental (serum/TGF-β) or oncogenetic (MYC) factors. Both TGF-β- and MYC-induced EMT required ZEB1, but engaged distinct TGF-β-dependent and vitamin D receptor-dependent (VDR-dependent) pathways, respectively. Functionally, we found that ZEB1 causally promotes malignant progression of HBECs and tumorigenicity, invasion, and metastases in non-small cell lung cancer (NSCLC) lines. Mechanistically, ZEB1 expression in HBECs directly repressed epithelial splicing regulatory protein 1 (ESRP1), leading to increased expression of a mesenchymal splice variant of CD44 and a more invasive phenotype. In addition, ZEB1 expression in early stage IB primary NSCLC correlated with tumor-node-metastasis stage. These findings indicate that ZEB1-induced EMT and associated molecular changes in ESRP1 and CD44 contribute to early pathogenesis and metastatic potential in established lung cancer. Moreover, TGF-β and VDR signaling and CD44 splicing pathways associated with ZEB1 are potential EMT chemoprevention and therapeutic targets in NSCLC.
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                Author and article information

                Contributors
                taoyong@csu.edu.cn
                shihongcan@hotmail.com
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                13 March 2018
                May 2018
                : 9
                : 5 ( doiID: 10.1111/tca.2018.9.issue-5 )
                : 589-597
                Affiliations
                [ 1 ] Department of Thoracic Surgery Second Xiangya Hospital of Central South University Hunan China
                [ 2 ] Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Xiangya Hospital, Central South University Hunan China
                [ 3 ] Key Laboratory of Carcinogenesis, Ministry of Health Cancer Research Institute, Central South University Hunan China
                [ 4 ] Institutes of Medical Sciences Xiangya Hospital, Central South University Hunan China
                [ 5 ] Department of Cardiothoracic Surgery Clinical College of Yangzhou University Jiangsu China
                Author notes
                [*] [* ] Correspondence

                Yongguang Tao, Key Laboratory of Carcinogenesis, Ministry of Health, Cancer Research Institute, Central South University, No. 110 Xiangya Road, Hunan 410078, China.

                Tel: +86 731 8480 5448

                Fax: +86 731 8447 0589

                Email: taoyong@ 123456csu.edu.cn

                Hongcan Shi, Department of Cardiothoracic Surgery, Clinical College of Yangzhou University, No. 11 Huaihai Road, Jiangsu 225001, China.

                Tel: +86 137 7350 9868

                Fax: +86 514 8797 8801

                Email: shihongcan@ 123456hotmail.com

                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0003-2354-5321
                Article
                TCA12623
                10.1111/1759-7714.12623
                5928388
                29532622
                fb3937e8-415a-459f-bdb6-4fc1b205a455
                © 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 24 January 2018
                : 07 February 2018
                : 08 February 2018
                Page count
                Figures: 4, Tables: 1, Pages: 9, Words: 5333
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81672787, 81370118, 81672308
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                tca12623
                May 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.7.2 mode:remove_FC converted:01.05.2018

                lncrna,metastasis,migration and invasion,nsclc,prognostic marker

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