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      Lentivirus-mediated knockdown of NLK inhibits small-cell lung cancer growth and metastasis

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          Abstract

          Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, has been recognized as a critical regulator of various cancers. In this study, we investigated the role of NLK in human small-cell lung cancer (SCLC), which is the most aggressive form of lung cancer. NLK expression was evaluated by quantitative real-time polymerase chain reaction in 20 paired fresh SCLC tissue samples and found to be noticeably elevated in tumor tissues. Lentivirus-mediated RNAi efficiently suppressed NLK expression in NCI-H446 cells, resulting in a significant reduction in cell viability and proliferation in vitro. Moreover, knockdown of NLK led to cell cycle arrest at the S-phase via suppression of Cyclin A, CDK2, and CDC25A, which could contribute to cell growth inhibition. Furthermore, knockdown of NLK decreased the migration of NCI-H446 cells and downregulated matrix metalloproteinase 9. Treatment with NLK short hairpin RNA significantly reduced SCLC tumor growth in vivo. In conclusion, this study suggests that NLK plays an important role in the growth and metastasis of SCLC and may serve as a potential therapeutic target for the treatment of SCLC.

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          Most cited references 21

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          Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs).

          All eukaryotic cells possess similar mechanisms to regulate the progression of the cell cycle. However, higher eukaryotes have evolved to respond to a large array of positive and negative signals with an intracellular or extracellular origin. These signals are eventually integrated by a conserved protein engine consisting of holoenzymes with kinase activity, which trigger crucial transitions during the cell cycle. In this review, the mechanisms by which the mammalian cell cycle engine integrates intracellular and extracellular signals of different nature are discussed.
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            Cutting edge: microRNA-181 promotes human NK cell development by regulating Notch signaling.

            MicroRNAs (miRs) have recently been identified as important regulators of gene expression at the posttranscriptional level. Although it has clearly been established that miRs influence the ontogeny of several immune cell lineages, the role of individual miRs during NK cell development has not been described. In this study, we show that miR-181 expression levels have a profound impact on the development of human NK cells from CD34(+) hematopoietic progenitor cells and IFN-γ production in primary CD56(+) NK cells. We also demonstrate that nemo-like kinase (NLK), an inhibitor of Notch signaling, is a target of miR-181 in NK cells, and knockdown of NLK mirrors the developmental effect of miR-181 overexpression. We conclude that miR-181 promotes NK cell development, at least in part, through the suppression of NLK, providing an important link between miRs and Notch signaling.
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              Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis.

              In eukaryotic cells, control mechanisms of cell-cycle progression have evolved to accurately monitor the integrity of genetic information to be transferred to the progeny. Cdc25A phosphatase is an essential activator of cell-cycle progression and is targeted by checkpoint signals. Ubiquitylation regulates Cdc25A activity through fine tuning of its protein levels. Two different ubiquitin ligases (APC/C and SCF complex) are involved in Cdc25A turnover. While APC/C is involved in regulating Cdc25A at the exit of mitosis, SCF regulates the abundance of Cdc25A in S phase and G2. In response to DNA damage or to stalled replication, the activation of the ATM and ATR protein kinases leads to Chk1 and Chk2 activation and to Cdc25A hyperphosphorylation. These events stimulate SCF-mediated ubiquitylation of Cdc25A and its proteolysis. This contributes to delaying cell-cycle progression, thereby preventing genomic instability. Based on recent findings, we discuss the role of Cdc25A ubiquitylation and degradation in cell-cycle progression and in response to DNA damage. Moreover, we discuss the role of phosphorylation at multiple sites in triggering ubiquitylation signals.
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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
                15 November 2016
                : 10
                : 3737-3746
                Affiliations
                [1 ]Department of Nuclear Medicine
                [2 ]Molecular Oncology Laboratory of Cancer Research Institute, The First Affiliated Hospital of China Medical University
                [3 ]Department of Pathology, The First Affiliated Hospital, College of Basic Medical Sciences of China Medical University
                [4 ]Department of Pathology, Institute of Pathology and Pathophysiology
                [5 ]Department of Immunology and Biotherapy, Liaoning Cancer Hospital and Institute
                [6 ]Department of Laboratory Medicine
                [7 ]Department of Rheumatology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
                Author notes
                Correspondence: Yaming Li, Department of Nuclear Medicine, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Shenyang 110001, People’s Republic of China, Tel +86 24 8328 2142, Fax +86 24 8328 2671, Email ymli2001@ 123456163.com
                Article
                dddt-10-3737
                10.2147/DDDT.S87435
                5117896
                © 2016 Lv 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.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                migration, nlk, proliferation, rnai, sclc

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