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      Cyclophilin A promotes non‐small cell lung cancer metastasis via p38 MAPK

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          Abstract

          Background

          Cyclophilin A (CypA) is associated with metastasis in diverse cancers; however, its role in lung cancer metastasis and the underlying mechanisms remain poorly understood. Our study investigated the effect of CypA on non‐small cell lung cancer (NSCLC) metastasis in vitro and in vivo to determine its mechanisms.

          Methods

          In this study, A549 and H1299 cell lines with downregulated and overexpressed CypA, respectively, were constructed by lentivirus transfection of NSCLC cells. in vitro experiments, including wound healing and transwell assays and Western blotting, showed that CypA promoted cancer cell migration and epithelial‐mesenchymal transition in NSCLC. Lung metastasis mouse models were used for the first time to confirm that CypA promoted NSCLC metastasis in vivo. The p38 inhibitor SB203580 was used to show that p38 MAPK is involved in CypA‐mediated NSCLC metastasis.

          Results

          Wound healing and transwell assays showed that the migration of both A549 and H1299 cells decreased in the CypA downregulated group and increased in the CypA overexpressed group. CypA also positively promoted the expression of epithelial‐mesenchymal transition‐relevant proteins. Results of mouse models confirmed that the tumor metastasis rate was much higher in the CypA overexpressed than in the CypA downregulated group. In addition, SB203580 inhibited NSCLC cell migration significantly in the CypA overexpressed group, while the difference in the CypA downregulated group was not significant.

          Conclusions

          In conclusion, this study demonstrated that CypA promotes NSCLC cancer metastasis via p38 MAPK.

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          Most cited references27

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          An osmosensing signal transduction pathway in yeast.

          Yeast genes were isolated that are required for restoring the osmotic gradient across the cell membrane in response to increased external osmolarity. Two of these genes, HOG1 and PBS2, encode members of the mitogen-activated protein kinase (MAP kinase) and MAP kinase kinase gene families, respectively. MAP kinases are activated by extracellular ligands such as growth factors and function as intermediate kinases in protein phosphorylation cascades. A rapid, PBS2-dependent tyrosine phosphorylation of HOG1 protein occurred in response to increases in extracellular osmolarity. These data define a signal transduction pathway that is activated by changes in the osmolarity of the extracellular environment.
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            A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells.

            Mammalian cells respond to endotoxic lipopolysaccharide (LPS) by activation of protein kinase cascades that lead to new gene expression. A protein kinase, p38, that was tyrosine phosphorylated in response to LPS, was cloned. The p38 enzyme and the product of the Saccharomyces cerevisiae HOG1 gene, which are both members of the mitogen-activated protein (MAP) kinase family, have sequences at and adjacent to critical phosphorylation sites that distinguish these proteins from most other MAP kinase family members. Both HOG1 and p38 are tyrosine phosphorylated after extracellular changes in osmolarity. These findings link a signaling pathway in mammalian cells with a pathway in yeast that is responsive to physiological stress.
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              MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer.

              Although cell invasion is a necessary early step in cancer metastasis, its regulation is not well understood. We have previously shown, in human prostate cancer, that transforming growth factor beta (TGFbeta)-mediated increases in cell invasion are dependent upon activation of the serine/threonine kinase, p38 MAP kinase. In the current study, downstream effectors of p38 MAP kinase were sought by first screening for proteins phosphorylated after TGFbeta treatment, only in the absence of chemical inhibitors of p38 MAP kinase. This led us to investigate mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2), a known substrate of p38 MAP kinase, as well as heat-shock protein 27 (HSP27), a known substrate of MAPKAPK2, in both PC3 and PC3-M human prostate cells. After transient transfection, wild-type MAPKAPK2 and HSP27 both increased TGFbeta-mediated matrix metalloproteinase type 2 (MMP-2) activity, as well as cell invasion, which in turn was inhibited by SB203580, an inhibitor of p38 MAP kinase. Conversely, dominant-negative MAPKAPK2 blocked phosphorylation of HSP27, whereas dominant-negative MAPKAPK2 or mutant, non-phosphorylateable, HSP27 each blocked TGFbeta-mediated increases in MMP-2, as well as cell invasion. Similarly, knock down of MAPKAPK2, HSP27 or both together, by siRNA, also blocked TGFbeta-mediated cell invasion. This study demonstrates that both MAPKAPK2 and HSP27 are necessary for TGFbeta-mediated increases in MMP-2 and cell invasion in human prostate cancer.
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                Author and article information

                Contributors
                shaofa_xu@hotmail.com
                yuewt@ccmu.edu.cn
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                07 November 2017
                January 2018
                : 9
                : 1 ( doiID: 10.1111/tca.2018.9.issue-1 )
                : 120-128
                Affiliations
                [ 1 ] Department of Cellular and Molecular Biology Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute Beijing China
                [ 2 ] Department of Thoracic Surgery Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute Beijing China
                Author notes
                [*] [* ] Correspondence

                Shaofa Xu, Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, 9#, Beiguan Street, Tongzhou, Beijing 101149, China.

                Tel: +86 10 8950 9181

                Fax: +86 10 8050 7349

                Email: shaofa_xu@ 123456hotmail.com

                Wentao Yue, Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institution, 9#, Beiguan Street, Tongzhou, Beijing 101149, China.

                Tel: +86 10 8950 9372

                Fax: +86 10 8050 7349

                Email: yuewt@ 123456ccmu.edu.cn

                Author information
                http://orcid.org/0000-0002-9595-7870
                Article
                TCA12548
                10.1111/1759-7714.12548
                5754294
                29110442
                01f105b5-c019-4978-b4f6-aa6b21f3b714
                © 2017 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 Creative Commons Attribution‐NonCommercial 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
                : 23 August 2017
                : 26 September 2017
                : 26 September 2017
                Page count
                Figures: 5, Tables: 0, Pages: 9, Words: 4427
                Funding
                Funded by: The National Natural Science Foundation of China
                Award ID: 81672838
                Funded by: The Capital Health Research and Development of Special
                Award ID: 2014‐2‐1041
                Funded by: The Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding
                Award ID: XMLX201705
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                tca12548
                January 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:04.01.2018

                cyclophilin a (cypa),metastasis,non‐small cell lung cancer (nsclc),p38 mapk

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