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      Deducting MicroRNA-Mediated Changes Common in Bronchial Epithelial Cells of Asthma and Chronic Obstructive Pulmonary Disease—A Next-Generation Sequencing-Guided Bioinformatic Approach

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          Abstract

          Asthma and chronic obstructive pulmonary disease (COPD) are chronic airway inflammatory diseases that share some common features, although these diseases are somewhat different in etiologies, clinical features, and treatment policies. The aim of this study is to investigate the common microRNA-mediated changes in bronchial epithelial cells of asthma and COPD. The microRNA profiles in primary bronchial epithelial cells from asthma (AHBE) and COPD (CHBE) patients and healthy subjects (NHBE) were analyzed with next-generation sequencing (NGS) and the significant microRNA changes common in AHBE and CHBE were extracted. The upregulation of hsa-miR-10a-5p and hsa-miR-146a-5p in both AHBE and CHBE was confirmed with quantitative polymerase chain reaction (qPCR). Using bioinformatic methods, we further identified putative targets of these microRNAs, which were downregulated in both AHBE and CHBE: miR-10a-5p might suppress BCL2, FGFR3, FOXO3, PDE4A, PDE4C, and PDE7A; miR-146a-5p might suppress BCL2, INSR, PDE4D, PDE7A, PDE7B, and PDE11A. We further validated significantly decreased expression levels of FOXO3 and PDE7A in AHBE and CHBE than in NHBE with qPCR. Increased serum miR-146a-5p level was also noted in patients with asthma and COPD as compared with normal control subjects. In summary, our study revealed possible mechanisms mediated by miR-10a-5p and miR-146a-5p in the pathogenesis of both asthma and COPD. The findings might provide a scientific basis for developing novel diagnostic and therapeutic strategies.

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          The emerging roles of forkhead box (Fox) proteins in cancer.

          Forkhead box (Fox) proteins are a superfamily of evolutionarily conserved transcriptional regulators, which control a wide spectrum of biological processes. As a consequence, a loss or gain of Fox function can alter cell fate and promote tumorigenesis as well as cancer progression. Here we discuss the evidence that the deregulation of Fox family transcription factors has a crucial role in the development and progression of cancer, and evaluate the emerging role of Fox proteins as direct and indirect targets for therapeutic intervention, as well as biomarkers for predicting and monitoring treatment responses.
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            Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids.

            Airway inflammation and epithelial remodeling are two key features of asthma. IL-13 and other cytokines produced during T helper type 2 cell-driven allergic inflammation contribute to airway epithelial goblet cell metaplasia and may alter epithelial-mesenchymal signaling, leading to increased subepithelial fibrosis or hyperplasia of smooth muscle. The beneficial effects of corticosteroids in asthma could relate to their ability to directly or indirectly decrease epithelial cell activation by inflammatory cells and cytokines. To identify markers of epithelial cell dysfunction and the effects of corticosteroids on epithelial cells in asthma, we studied airway epithelial cells collected from asthmatic subjects enrolled in a randomized controlled trial of inhaled corticosteroids, from healthy subjects and from smokers (disease control). By using gene expression microarrays, we found that chloride channel, calcium-activated, family member 1 (CLCA1), periostin, and serine peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2) were up-regulated in asthma but not in smokers. Corticosteroid treatment down-regulated expression of these three genes and markedly up-regulated expression of FK506-binding protein 51 (FKBP51). Whereas high baseline expression of CLCA1, periostin, and serpinB2 was associated with a good clinical response to corticosteroids, high expression of FKBP51 was associated with a poor response. By using airway epithelial cells in culture, we found that IL-13 increased expression of CLCA1, periostin, and serpinB2, an effect that was suppressed by corticosteroids. Corticosteroids also induced expression of FKBP51. Taken together, our findings show that airway epithelial cells in asthma have a distinct activation profile and identify direct and cell-autonomous effects of corticosteroid treatment on airway epithelial cells that relate to treatment responses and can now be the focus of specific mechanistic studies.
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              Hypoxic Lung-Cancer-Derived Extracellular Vesicle MicroRNA-103a Increases the Oncogenic Effects of Macrophages by Targeting PTEN

              Hypoxia, the most commonly observed characteristic in cancers, is implicated in the establishment of an immunosuppressive niche. Recent studies have indicated that extracellular vesicle (EV)-mediated cancer-stroma interactions are considered to play a critical role in the regulation of various cellular biological functions, with phenotypic consequences in recipient cells. However, the mechanisms underlying the relationship between EVs and hypoxia during cancer progression remain largely unknown. In this study, we found that EVs derived from hypoxic lung cancers increased M2-type polarization by miR-103a transfer. Decreased PTEN levels caused by hypoxic cancer-cell-derived EV miR-103a increased activation of AKT and STAT3 as well as expression of several immunosuppressive and pro-angiogeneic factors. In contrast, inhibition of miR-103a by an miRNA inhibitor effectively decreased hypoxic cancer-mediated M2-type polarization, improving the cytokine prolife of tumor infiltration macrophages. Macrophages received cancer-cell-derived EV miR-103a feedback to further enhance cancer progression and tumor angiogenesis. Finally, circulating EV miR-103a levels were higher in patients with lung cancer and closely associated with the M2 polarization. In conclusion, our results delineate a novel mechanism by which lung cancer cells induce immunosuppressive and pro-tumoral macrophages through EVs and inspire further research into the clinical application of EV inhibition or PTEN restoration for immunotherapy.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                28 January 2019
                February 2019
                : 20
                : 3
                : 553
                Affiliations
                [1 ]Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 807 Kaohsiung, Taiwan; SiegfriedTsai@ 123456gmail.com (M.-J.T.); 1010362KMUH@ 123456gmail.com (Y.-C.T.); 960215kmuh@ 123456gmail.com (W.-A.C.); ysirenelin@ 123456gmail.com (Y.-S.L.); kanginbobo@ 123456gmail.com (P.-H.T.); sheucc@ 123456gmail.com (C.-C.S.)
                [2 ]Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, 807 Kaohsiung, Taiwan
                [3 ]Department of Respiratory Therapy, School of Medicine, College of Medicine, Kaohsiung Medical University, 807 Kaohsiung, Taiwan
                [4 ]Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, 807 Kaohsiung, Taiwan; kuopolin@ 123456seed.net.tw
                [5 ]Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, 807 Kaohsiung, Taiwan
                Author notes
                [* ]Correspondence: hsuyl326@ 123456gmail.com ; Tel.: +886-7-3121101 (ext. 2136, ext. 26)
                Author information
                https://orcid.org/0000-0003-3621-3334
                https://orcid.org/0000-0002-7979-3749
                https://orcid.org/0000-0003-2487-2818
                Article
                ijms-20-00553
                10.3390/ijms20030553
                6386886
                30696075
                0e3c08e4-12ea-475b-a480-49e548c2e92f
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 08 December 2018
                : 26 January 2019
                Categories
                Article

                Molecular biology
                asthma,copd,epithelium,bronchial epithelial cells,next-generation sequencing,bioinformatics

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