DOCSLIB.ORG

Increased S100A15 Expression and Decreased DNA Methylation of Its Gene Promoter Are Involved in High Metastasis Potential and Poor Outcome of Lung Adenocarcinoma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Increased S100A15 Expression and Decreased DNA Methylation of Its Gene Promoter Are Involved in High Metastasis Potential and Poor Outcome of Lung Adenocarcinoma www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 28), pp: 45710-45724 Research Paper Increased S100A15 expression and decreased DNA methylation of its gene promoter are involved in high metastasis potential and poor outcome of lung adenocarcinoma Yung-Che Chen1,6,*, Meng-Chih Lin1,6,*, Chang-Chun Hsiao6,7, Yi-Xin Zheng1, Kuang- Den Chen2, Ming-Tse Sung3, Chung-Jen Chen4, Ting-Ya Wang1, Yong-Yong Lin1, Huang-Chih Chang1,6, Yu-Mu Chen1 and Jen-Chieh Chang5 1Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 2Center of Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 3Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 4Division of Rheumatology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 5Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 6Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 7Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan *These authors have contributed equally to this work Correspondence to: Yung-Che Chen, email: [email protected] Meng-Chih Lin, email: [email protected] Chang-Chun Hsiao, email: [email protected] Keywords: lung adenocarcinoma, S100A15, DNA methylation, next generation sequencing Received: November 02, 2016 Accepted: April 10, 2017 Published: April 24, 2017 Copyright: Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Purpose: This study aims to determine the functional role of S100A15 and its promoter DNA methylation patterns in lung cancer progression. Experimental Design: We analyzed 178 formalin-fixed paraffin embedded specimens from lung cancer patients, including 24 early stage and 91 advanced stage adenocarcinoma. S100A15 protein expression was evaluated by immunohistochemistry stain, and its DNA methylation levels were measured by pyrosequencing. Results: S100A15 nuclear staining was increased in lung adenocarcinoma patients with distant metastasis versus those without distant metastasis. There was reduced one/three-year overall survival in adenocarcinoma patients receiving first line target therapy and harboring high nuclear expressions of S100A15. Both DNA methylation levels over -423 and -248 CpG sites of the S100A15 gene promoter were decreased in adenocarcinoma patients with distant metastasis, and the former was associated with lower one-year overall survival. The highly invasive CL1-5 cell lines display decreased DNA methylation over –412/-248/-56 CpG sites of the S100A15 gene promoter and increased S100A15 gene/protein expressions as compared with the less invasive CL1-0 cell lines. Knockdown of S100A15 in CL1-5 cell line inhibited cell proliferation, migration, and invasion, while over-expression of S100A15 in CL1-0 cell line promoted cell proliferation, migration, and invasion. RNA sequencing analysis revealed potential www.impactjournals.com/oncotarget 45710 Oncotarget biological effects of S100A15 over-expression and knock-down with CTNNB1, ZEB1, CDC42, HSP90AA1, BST2, and PCNA being the pivotal down-stream mediators. Conclusions: Increased S100A15 expression and decreased DNA methylation of its gene promoter region were associated with high metastasis potential and poor outcome in lung adenocarcinoma, probably through triggering CTNNB1 -centered pathways. INTRODUCTION S100A15 on metastatic potential and down-stream mediators of lung adenocarcinoma was tested in vitro. The majority of non-small cell lung cancer patients present with advanced disease at diagnosis, and those RESULTS diagnosed with early stage disease often recur and experience metastatic disease eventually [1]. Metastasis S100A15 nuclear accumulation was increased represents the primary cause of death from lung cancer, is in lung adenocarcinoma patients with distant responsible for 90% of all morbidity, and involves several metastasis, and related to poor survival in those stages, including invasion, angiogenesis, and migration. [2]. receiving first line target therapy Human S100A15 (S100A7A; koebnerisin) is a novel member of the S100 family of EF-hand calcium- S100A15 IHC nuclear stain were performed and binding proteins and was recently identified in psoriasis, evaluated in 178 pathologically-diagnosed lung cancer where it is significantly up-regulated in lesion skin. It is patients, including 115 cases (64.6%) of adenocarcinoma, an antimicrobial protein, and regulated by E. coli through 50 cases (28.1%) of squamous cell carcinoma, and 13 cases Toll-like receptor 4 [3]. Both human S100A7 (psoriasin) (7.3%) of small cell carcinoma. The demographic and clinical and S100A15 transcripts are elevated in ER/PR negative data of these subjects are presented in Table 1. Stepwise breast cancers; however, hS100A15 protein is detected in forward multivariate Cox regression analysis showed that all cancer specimens, while hS100A7 protein is sporadically advanced tumor stage (HR 3.149, 95%CI 1.719-5.761, expressed [4, 5]. C-Fos transcriptionally controls S100A15 p<0.001), first line use of cisplatin-based chemotherapy (HR expression in keratinocytes, subsequently leading to CD4 0.323, 95%CI 0.203-0.513, p<0.001), and first-line use of T-cell recruitment to the skin, thereby promoting epidermal target therapy with erlotinib or gefitinib (HR 0.608, 95%CI squamous cell carcinoma that is likely induced by CD4+ 0.373-0.992, p=0.046) were independent factors predicting T-cell-derived IL-22 [6]. In our previous whole-genome one-year all-cause mortality. Furthermore, advanced tumor gene expression study, we found that nuclear accumulation stage (HR 2.188, 95%CI 1.074-4.457, p=0.031), N2/3 (HR of S100A15 were increased in advanced stage NSCLC 3.343/5.946, 95%CI 1.871-5.975/3.107-11.879, p<0.001), patients [1], but the potential of S100A15 as a determinant M1 (HR 2.095, 95%CI 1.381-3.179, p=0.001), ECOG of treatment outcomes, and the underlying mechanisms by which S100A15 would be involved in proliferation, PS (HR 1.182, 95%CI 1.022-1.367, p=0.025), first line migration, and invasion of lung cancer have not yet been use of cisplatin-based chemotherapy (HR 0.492, 95% CI understood [1, 7]. DNA methylation changes induced 0.333-0.728, p<0.001), and second line use of pemetrexed in oncogenes and tumor suppressor genes are of key chemotherapy (HR 0.214, 95% CI 0.064-0.712, p=0.012) are importance in the pathogenesis of lung cancer [8, 9]. Recent independent factors predicting three-year all-cause mortality. results indicate that changes in S100 protein expression In the 115 lung adenocarcinoma cases, total may depend on the extent of DNA methylation in the S100 score (4.77±1.1 versus 3.75±1.48, adjusted p=0.002, gene promoter regions [10]. The role of DNA methylation 95%CI 0.126-0.538), intensity score (1.56±0.56 versus patterns of the S100A15 promoter region in metastasis 1.29±0.55, adjusted p=0.025, 95%CI 0.015-0.209), and potential of lung cancer has not yet been determined [11]. percentage score (3.18±0.8 versus 2.46±1.14, adjusted We retrospectively examined S100A15 protein p<0.001, 95%CI 2.42-7.876) of S100A15 nuclear stain expression, as determined by immunohistochemistry (IHC) were all significantly increased in patients with advanced stain, in a cohort of 178 subjects with NSCLC diagnosed stage tumor (stage IIIB and IV, n = 91) compared with through bronchoscopy-guided biopsy, and correlated it with that in those with early stage tumor (stage I - IIIA, n their clinical characteristics, including tumor stage (TNM = 24, Figure 1A-C). Likewise, total score (4.79±1.14 staging), treatment response, and overall survival (1- and versus 4.05±1.34, adjusted p=0.012, 95%CI 0.154- 3-year). DNA methylation levels of 5 CpG sites over the 1.217), intensity score (1.52±0.57 versus 1.35±0.53, S100A15 gene promoter region and 1 CpG site over exon adjusted p=0.035, 95%CI 0.017-0.47), and percentage 1 of the S100A15 gene were measured in 51 DNA samples score (3.18±0.81 versus 2.68±1.04, adjusted p=0.041, extracted from the formalin fixed paraffin-embedded (FFPE) 95%CI 0.017-0.797) of S100A15 nuclear stain were tissues of lung adenocarcinoma. Furthermore, S100A15 significantly increased in lung adenocarcinoma patients expression and its gene promoter DNA methylation levels with distant metastasis (M1, n=77) as compared with in lung cancer cell lines were measured, and the effect of that in those without distant metastasis (M0, n=38, www.impactjournals.com/oncotarget 45711 Oncotarget Table 1: Baseline and clinical characteristics of all the lung cancer patients All Lung cancer Early stage (I-IIIA), Advanced stage P value* patients, N=178 Lung AC patients, (IIIB-IV), Lung AC N=24 patients, N = 91 Age, years 66.7±8.3 63.8±12 0.268 Male, n (%) 115 (64.6) 11 (45.8) 49 (53.8) 0.48 Smoking history, n (%) 57 (34) 5 (20.9) 24 (26.4) 0.426 TNM stage, n (%) T1 15 (8.4) 5 (20.8) 5 (5.5) <0.001 T2 67 (37.6) 16 (66.7) 31 (34.1) T3 17 (9.6) 1 (4.2) 8 (8.8) T4 79 (44.4) 2 (8.3) 47 (51.6) N0 33 (18.5) 14 (58.3) 10 (11) <0.001 N1 23 (12.9) 1 (4.2) 15 (16.5) N2 74 (41.6) 9 (37.5) 37 (40.7) N3 48 (27) 0 (0) 29 (31.9) M0 62 (35) 24 (100) 14 (15.38) <0.001 M1 116 (65) 0 (0) 77 (84.6) ECOG PS 0.003 0 36 (20.2) 11 (45.8) 14 (15.4) 1 85 (47.8) 11 (45.8) 45 (49.5) 2 27 (15.2) 0 (0) 18 (19.8) 3 13 (7.3) 2 (8.3) 4 (4.4) 4 17 (9.6) 0 (0) 10 (11) AC = adenocarcinoma; PS = performance status *Compared between early stage and advanced stage lung AC patients Figure 1D-F).
Load more

Recommended publications
  • S100A7 Promotes the Migration and Invasion of Osteosarcoma Cells Via the Receptor for Advanced Glycation End Products
    ONCOLOGY LETTERS 3: 1149-1153, 2012 S100A7 promotes the migration and invasion of osteosarcoma cells via the receptor for advanced glycation end products KEN KATAOKA*, TOMOYUKI ONO*, HITOSHI MURATA, MIKA MORISHITA, KEN-ICHI YAMAMOTO, MASAKIYO SAKAGUCHI and NAM-HO HUH Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan Received December 14, 2011; Accepted February 1, 2012 DOI: 10.3892/ol.2012.612 Abstract. Osteosarcoma is the most common malignant tumor significantly improved the 5-year survival rate of osteosarcoma of bone in childhood and adolescence. Despite intensive patients from 15 to 70% (2). However, 30-40% of patients still research for new therapies, the outcome in patients with metas- succumb to the disease, mainly due to distant metastasis to tasis remains extremely poor. S100 proteins are involved in the the lung (3). Despite intensive research for new therapies, the proliferation, cell cycle progression and metastasis of numerous outcome in patients with metastasis remains extremely poor. malignant tumors, including osteosarcoma. In the present study, The S100 protein family consists of 20 calcium-binding we identified S100A7 as a candidate to promote the migra- proteins with EF hand motifs (4). S100 proteins have been tion of osteosarcoma cells. S100A7 promoted the migration shown to have intracellular and extracellular roles in the regula- and invasion of osteosarcoma cells as assayed in vitro. An in tion of diverse processes, including protein phosphorylation, vitro pull-down assay revealed the binding of the recombinant cell growth and motility, cell-cycle regulation, transcription, S100A7 protein with its putative receptor, the receptor for differentiation and cell survival (5).
    [Show full text]
  • Inflammation-Mediated Skin Tumorigenesis Induced by Epidermal C-Fos
    Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Inflammation-mediated skin tumorigenesis induced by epidermal c-Fos Eva M. Briso,1 Juan Guinea-Viniegra,1 Latifa Bakiri,1 Zbigniew Rogon,2 Peter Petzelbauer,3 Roland Eils,2 Ronald Wolf,4 Mercedes Rinco´ n,5 Peter Angel,6 and Erwin F. Wagner1,7 1BBVA Foundation-Spanish National Cancer Research Center (CNIO) Cancer Cell Biology Program, CNIO, 28029 Madrid, Spain; 2Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; 3Skin and Endothelium Research Division (SERD), Department of Dermatology, Medical University of Vienna, A-1090 Vienna, Austria; 4Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany; 5Division of Immunobiology, Department of Medicine, University of Vermont, 05405 Burlington, Vermont, USA; 6Division of Signal Transduction and Growth Control, DKFZ, DKFZ-Center for Molecular Biology of the University of Heidelberg (ZMBH) Alliance, 69120 Heidelberg, Germany Skin squamous cell carcinomas (SCCs) are the second most prevalent skin cancers. Chronic skin inflammation has been associated with the development of SCCs, but the contribution of skin inflammation to SCC development remains largely unknown. In this study, we demonstrate that inducible expression of c-fos in the epidermis of adult mice is sufficient to promote inflammation-mediated epidermal hyperplasia, leading to the development of preneoplastic lesions. Interestingly, c-Fos transcriptionally controls mmp10 and s100a7a15 expression in keratinocytes, subsequently leading to CD4 T-cell recruitment to the skin, thereby promoting epidermal hyperplasia that is likely induced by CD4 T-cell-derived IL-22. Combining inducible c-fos expression in the epidermis with a single dose of the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) leads to the development of highly invasive SCCs, which are prevented by using the anti-inflammatory drug sulindac.
    [Show full text]
  • (Rage) in Progression of Pancreatic Cancer
    The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 8-2017 INVOLVEMENT OF THE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) IN PROGRESSION OF PANCREATIC CANCER Nancy Azizian MS Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Biology Commons, and the Medicine and Health Sciences Commons Recommended Citation Azizian, Nancy MS, "INVOLVEMENT OF THE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) IN PROGRESSION OF PANCREATIC CANCER" (2017). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 748. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/748 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. INVOLVEMENT OF THE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (RAGE) IN PROGRESSION OF PANCREATIC CANCER by Nancy
    [Show full text]
  • Comparative Genomics Search for Losses of Long-Established Genes on the Human Lineage
    Comparative Genomics Search for Losses of Long-Established Genes on the Human Lineage Jingchun Zhu1, J. Zachary Sanborn1, Mark Diekhans1, Craig B. Lowe1, Tom H. Pringle1, David Haussler1,2* 1 Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America, 2 Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, California, United States of America Taking advantage of the complete genome sequences of several mammals, we developed a novel method to detect losses of well-established genes in the human genome through syntenic mapping of gene structures between the human, mouse, and dog genomes. Unlike most previous genomic methods for pseudogene identification, this analysis is able to differentiate losses of well-established genes from pseudogenes formed shortly after segmental duplication or generated via retrotransposition. Therefore, it enables us to find genes that were inactivated long after their birth, which were likely to have evolved nonredundant biological functions before being inactivated. The method was used to look for gene losses along the human lineage during the approximately 75 million years (My) since the common ancestor of primates and rodents (the euarchontoglire crown group). We identified 26 losses of well-established genes in the human genome that were all lost at least 50 My after their birth. Many of them were previously characterized pseudogenes in the human genome, such as GULO and UOX. Our methodology is highly effective at identifying losses of single-copy genes of ancient origin, allowing us to find a few well-known pseudogenes in the human genome missed by previous high-throughput genome-wide studies.
    [Show full text]
  • Structural Characterization of S100A15 Reveals a Novel Zinc Coordination
    Murray et al. BMC Structural Biology 2012, 12:16 http://www.biomedcentral.com/1472-6807/12/16 RESEARCH ARTICLE Open Access Structural characterization of S100A15 reveals a novel zinc coordination site among S100 proteins and altered surface chemistry with functional implications for receptor binding Jill I Murray1,2, Michelle L Tonkin2, Amanda L Whiting1, Fangni Peng2, Benjamin Farnell1,2, Jay T Cullen3, Fraser Hof1 and Martin J Boulanger2* Abstract Background: S100 proteins are a family of small, EF-hand containing calcium-binding signaling proteins that are implicated in many cancers. While the majority of human S100 proteins share 25-65% sequence similarity, S100A7 and its recently identified paralog, S100A15, display 93% sequence identity. Intriguingly, however, S100A7 and S100A15 serve distinct roles in inflammatory skin disease; S100A7 signals through the receptor for advanced glycation products (RAGE) in a zinc-dependent manner, while S100A15 signals through a yet unidentified G-protein coupled receptor in a zinc-independent manner. Of the seven divergent residues that differentiate S100A7 and S100A15, four cluster in a zinc-binding region and the remaining three localize to a predicted receptor-binding surface. Results: To investigate the structural and functional consequences of these divergent clusters, we report the X-ray crystal structures of S100A15 and S100A7D24G, a hybrid variant where the zinc ligand Asp24 of S100A7 has been substituted with the glycine of S100A15, to 1.7 Å and 1.6 Å resolution, respectively. Remarkably, despite replacement of the Asp ligand, zinc binding is retained at the S100A15 dimer interface with distorted tetrahedral geometry and a chloride ion serving as an exogenous fourth ligand.
    [Show full text]
  • Probing the S100 Protein Family Through Genomic and Functional Analysis$
    Genomics 84 (2004) 10–22 www.elsevier.com/locate/ygeno Probing the S100 protein family through genomic and functional analysis$ Timothy Ravasi,a,b,* Kenneth Hsu,c Jesse Goyette,c Kate Schroder,a Zheng Yang,c Farid Rahimi,c Les P. Miranda,b,1 Paul F. Alewood,b David A. Hume,a,b and Carolyn Geczyc a SRC for Functional and Applied Genomics, CRC for Chronic Inflammatory Diseases, University of Queensland, Brisbane 4072, QLD, Australia b Institute for Molecular Bioscience, University of Queensland, Brisbane 4072, QLD, Australia c Cytokine Research Unit, School of Medical Sciences, University of New South Wales, Sydney 2052, NSW, Australia Received 25 November 2003; accepted 2 February 2004 Available online 10 May 2004 Abstract The EF-hand superfamily of calcium binding proteins includes the S100, calcium binding protein, and troponin subfamilies. This study represents a genome, structure, and expression analysis of the S100 protein family, in mouse, human, and rat. We confirm the high level of conservation between mammalian sequences but show that four members, including S100A12, are present only in the human genome. We describe three new members of the S100 family in the three species and their locations within the S100 genomic clusters and propose a revised nomenclature and phylogenetic relationship between members of the EF-hand superfamily. Two of the three new genes were induced in bone-marrow-derived macrophages activated with bacterial lipopolysaccharide, suggesting a role in inflammation. Normal human and murine tissue distribution profiles indicate that some members of the family are expressed in a specific manner, whereas others are more ubiquitous.
    [Show full text]
  • Functionally Distinct S100A15 Inflammation with Highly
    Chemotactic Activity of S100A7 (Psoriasin) Is Mediated by the Receptor for Advanced Glycation End Products and Potentiates Inflammation with Highly Homologous but This information is current as Functionally Distinct S100A15 of September 23, 2021. Ronald Wolf, O. M. Zack Howard, Hui-Fang Dong, Christopher Voscopoulos, Karen Boeshans, Jason Winston, Rao Divi, Michele Gunsior, Paul Goldsmith, Bijan Ahvazi, Triantafyllos Chavakis, Joost J. Oppenheim and Stuart H. Downloaded from Yuspa J Immunol 2008; 181:1499-1506; ; doi: 10.4049/jimmunol.181.2.1499 http://www.jimmunol.org/content/181/2/1499 http://www.jimmunol.org/ References This article cites 50 articles, 8 of which you can access for free at: http://www.jimmunol.org/content/181/2/1499.full#ref-list-1 Why The JI? Submit online. by guest on September 23, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Chemotactic Activity of S100A7 (Psoriasin) Is Mediated by the Receptor for Advanced Glycation End Products and Potentiates Inflammation with Highly Homologous but Functionally Distinct S100A151 Ronald Wolf,* O.
    [Show full text]
  • Evaluation of the Stimulatory Effects of EBC-46 on Dermal Fibroblast And
    Evaluation of the Stimulatory Effects of EBC-46 on Dermal Fibroblast and Keratinocyte Wound Healing Responses in Vitro and Correlation to Preferential Healing in Vivo Rachael Louise Moses BSc, MSc Thesis presented for the degree of Doctor of Philosophy Stem Cells, Wound Repair & Regeneration, Oral and Biomedical Sciences, Cardiff Institute of Tissue Engineering & Repair (CITER), School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK August, 2016 Dedication I would like to dedicate this thesis to my Mum, you have been an inspiration to me and given me every opportunity. I am truly thankful for your unconditional love and support, making this PhD possible. Thank you for always being there; I love you. ii Acknowledgements Firstly, I would like to give utmost thanks and appreciation to my two supervisors, Dr Ryan Moseley and Dr Robert Steadman. You have provided invaluable expertise, support, encouragement and enthusiasm throughout my project; I have thoroughly enjoyed this project. I have greatly appreciated your guidance and encouragement of my future career in research. In addition, I am hugely grateful to all who have assisted me and provided support from the School of Dentistry, Institute of Nephrology and Tenovus Building. Particular thanks go to Dr Adam Midgeley, who has provided vital support and advice on experimental procedures and subsequent analysis. I would like to thank Professor Rachel Errington, Dr Rachel Howard-Jones and Marie Wiltshire, their assistance and knowledge on flow cytometry procedures and the specialised analysis software was greatly appreciated. I would also like to thank the technical team at the School of Dentistry; who have all contributed to the successful running of the department, along with providing equipment expertise and knowledge.
    [Show full text]
  • Interferon Beta Activity Is Modulated Via Binding of Specific S100 Proteins
    International Journal of Molecular Sciences Article Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins Alexey S. Kazakov 1, Alexander D. Sofin 1, Nadezhda V. Avkhacheva 1, Alexander I. Denesyuk 1,2 , Evgenia I. Deryusheva 1, Victoria A. Rastrygina 1 , Andrey S. Sokolov 1, Maria E. Permyakova 1, Ekaterina A. Litus 1, Vladimir N. Uversky 1,3,* , Eugene A. Permyakov 1 and Sergei E. Permyakov 1,* 1 Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institutskaya str., 7, 142290 Pushchino, Russia; fenixfl[email protected] (A.S.K.); AlSofi[email protected] (A.D.S.); [email protected] (N.V.A.); adenesyu@abo.fi (A.I.D.); [email protected] (E.I.D.); certusfi[email protected] (V.A.R.); [email protected] (A.S.S.); [email protected] (M.E.P.); [email protected] (E.A.L.); [email protected] (E.A.P.) 2 Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520 Turku, Finland 3 Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA * Correspondence: [email protected] (V.N.U.); [email protected] (S.E.P.); Tel.: +7-(495)-143-7741 (S.E.P.); Fax: +7-(4967)-33-05-22 (S.E.P.) Received: 25 November 2020; Accepted: 11 December 2020; Published: 13 December 2020 Abstract: Interferon-β (IFN-β) is a pleiotropic cytokine used for therapy of multiple sclerosis, which is also effective in suppression of viral and bacterial infections and cancer.
    [Show full text]
  • Binding Profile Mapping of the S100 Protein Family Using a High-Throughput Local Surface Mimetic Holdup Assay
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.02.407676; this version posted December 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Binding Profile Mapping of the S100 Protein Family Using a High-throughput Local Surface Mimetic Holdup Assay Márton A. Simon1, 2, $, Éva Bartus3, 4 $, Beáta Mag3, Eszter Boros1, Lea Roszjár3, Gergő Gógl1, 5, Gilles Travé5, Tamás A. Martinek3, * and László Nyitray1, * 1Department of Biochemistry, Eötvös Loránd University, H-1117 Budapest, Hungary 2Department of Medical Biochemistry, Semmelweis University, H-1094 Budapest, Hungary 3Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Hungary 4MTA-SZTE Biomimetic Systems Research Group, University of Szeged, H-6720 Szeged, Hungary 5Equipe Labellisee Ligue 2015, Department of Integrated Structural Biology, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM U1258/CNRS UMR 7104/Universite de Strasbourg, 1 rue Laurent Fries, BP 10142, F-67404 Illkirch, France $These authors contributed equally *To whom correspondence should be addressed: Tamás A. Martinek, e-mail: [email protected], László Nyitray, e-mail: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.02.407676; this version posted December 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
    [Show full text]
  • S100A7 (Psoriasin) Is Induced by the Proinflammatory Cytokines
    Oncogene (2010) 29, 2083–2092 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc ORIGINAL ARTICLE S100A7 (psoriasin) is induced by the proinflammatory cytokines oncostatin-M and interleukin-6 in human breast cancer NR West1,2 and PH Watson1,2,3 1Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada; 2Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada and 3Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada S100A7 promotes aggressive features in breast cancer, sion, many tumors harbor chronically activated infil- although regulation of its expression is poorly understood. trates of innate immune cells and dysfunctional As S100A7 associates with inflammation in skin and breast lymphocytes that can support tumor progression (Balk- tissue, we hypothesized that inflammatory cytokines may will et al., 2005; de Visser et al., 2006; Zitvogel et al., regulate S100A7 in breast cancer. We therefore examined 2006). Tumors may use numerous mechanisms to the effects of several cytokines, among which oncostatin-M exploit immune activity, including adaptation and (OSM) and the related cytokine, interleukin (IL)-6, showed responsiveness to immune-derived cytokines. Inter- the most significant effects on S100A7 expression in breast leukin (IL)-6, for example, a prominent inflammatory tumor cells in vitro. Both cytokines consistently induced cytokine, was recently shown to promote spheroid S100A7 expression in three cell lines (MCF7, T47D and formation by breast tumor progenitor cells via Notch MDA-MB-468) in a dose- and time-dependent manner. signaling (Sansone et al., 2007).
    [Show full text]
  • Psoriasin (S100A7) and Koebnerisin (S100A15) in the Model of Inflammation: Functional Characterization in the Inflammation Cascade
    Aus der Klinik und Poliklinik für Dermatologie und Allergologie der Ludwig-Maximilians-Universität München Direktor: Prof. Dr. med. Dr. h.c. Thomas Ruzicka Psoriasin (S100A7) and koebnerisin (S100A15) in the model of inflammation: functional characterization in the inflammation cascade. Dissertation zum Erwerb des Doktorgrades der Humanbiologie an der Medizinischen Fakultät der Ludwig-Maximilians-Universität München vorgelegt von Stephanie Zwicker, M.Sc. aus Berlin 2014 - 2 - Mit Genehmigung der Medizinischen Fakultät der Ludwig-Maximilians-Universität München Berichterstatter: PD Dr. med. Ronald Wolf Mitberichterstatter: Prof. Dr. med. Dr. phil. Johannes Ring Prof. Dr. med. Hendrick Schulze-Koops Prof. Dr. med. Marc Heckmann Dekan: Prof. Dr. med. Dr. h.c. M. Reiser, FACR, FRCR Tag der mündlichen Prüfung: 30. Juli 2014 - 3 - Für meine Liebsten - 4 - - 5 - Life is what happens while you are busy making other plans. (Leben ist das, was passiert, während du dabei bist, andere Pläne zu schmieden.) John Lennon, 1940-1980 (British musician) - 6 - - 7 - Table of contents List of abbreviations ............................................................................................................... - 11 - 1. Introduction ....................................................................................................................... - 13 - 1.1 Structure and barrier function of human skin.................................................................... - 13 - 1.2 Innate and adaptive immunity in the skin ........................................................................
    [Show full text]