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Versican Upregulation in SÉZary Cells Alters Leukemia (2015) 29, 2024–2032 © 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15 www.nature.com/leu ORIGINAL ARTICLE Versican upregulation in Sézary cells alters growth, motility and resistance to chemotherapy K Fujii1,3, MB Karpova1,4, K Asagoe1,5, O Georgiev2, R Dummer1 and M Urosevic-Maiwald1 Sézary syndrome (SéS) represents a leukemic variant of cutaneous T-cell lymphoma, whose etiology is still unknown. To identify dyregulated genes in SéS, we performed transcriptional profiling of Sézary cells (SCs) obtained from peripheral blood of patients with SéS. We identified versican as the highest upregulated gene in SCs. VCAN is an extracellular matrix proteoglycan, which is known to interfere with different cellular processes in cancer. Versican isoform V1 was the most commonly upregulated isoform in SCs. Using a lentiviral plasmid, we overexpressed versican V1 isoform in lymphoid cell lines, which altered their growth behavior by promoting formation of smaller cell clusters and by increasing their migratory capacity towards stromal cell-derived factor 1, thus promoting skin homing. Versican V1 overexpression exerted an inhibitory effect on cell proliferation, partially by promoting activation-induced cell death. Furthermore, V1 overexpression in lymphoid cell lines increased their sensitivity to doxorubicin and gemcitabine. In conclusion, we confirm versican as one of the dysregulated genes in SéS and describe its effects on the biology of SCs. Although versican overexpression confers lymphoid cells with increased migratory capacity, it also makes them more sensitive to activation-induced cell death and some chemotherapeutics, which could be exploited further for therapeutic purposes. Leukemia (2015) 29, 2024–2032; doi:10.1038/leu.2015.103 INTRODUCTION In this study, we identified versican as one of the highest Sézary syndrome (SéS), a leukemic variant of cutaneous T-cell upregulated genes in SCs using high-throughput gene expression lymphoma (CTCL), is characterized by erythroderma, generalized profiling. Overexpression of versican V1 exhibited influence on lymphadenopathy and the presence of clonal T lymphocytes in growth and migration behavior, cell proliferation and suscept- the skin, lymph nodes and peripheral blood.1 Tumor cells of SéS, ibility to chemotherapy of lymphoid cells, providing first evidence called Sézary cells (SCs), harbor spectrum of genetic abnormalities on versican functionality in a leukemic T-cell lymphoma. as well as alterations in apoptotic pathways, lymphocyte differentiation and cytokine signaling.2 Various studies have MATERIALS AND METHODS attempted to clarify the exact pathogenic events in SéS; however, Biologic samples and cell lines the exact mechanisms underlying accumulation of malignant SCs Peripheral blood mononuclear cells (PBMCs) and skin biopsy samples from in the skin and other target organs are still poorly understood. five patients with SéS were a surplus material obtained during routine One molecule described in context of SéS is versican (VCAN, diagnostic procedures, for which the patients have given their written also known as PG-M and CSPG2), a member of the large consent and obtained approval of the institutional ethical committee. aggregating chondroitin sulfate (CS) proteoglycan family repre- PBMCs were obtained by Ficoll-density gradient centrifugation (Sigma- senting one of the major components of extracellular matrix Aldrich, St Louis, MO, USA). All patients fulfilled diagnostic criteria for 13 (ECM).2–4 Versican is expressed in a variety of soft tissues, SéS. Using magnetic labeling system on Macs cell sorter (Miltenyi Biotec, 5 α Bergisch Gladbach, Germany), SCs were separated by using CD4 − and including skin. Alternative splicing of the CS domain into CS fi β and CSβ generates four versican isoforms, V0, V1, V2 and V3. second by using patient clone-speci c T-cell receptor (TCR) V -chain antibody.14,15 In this way, highly purified CD4+Vβ+ SC population Overexpression of V1 in vitro results in enhanced cell proliferation was generated. The residual, non-malignant CD4+Vβ − cell population and protection from apoptosis.6 V1-overexpression can simulta- 7 was employed as an internal control in addition to CD4+ cells from healthy neously cause apoptotic resistance and sensitivity. On the other donors. hand, V2 and V3 exhibit opposite biological activities by inhibiting Three CTCL cell lines, MyLa (derived from a plaque biopsy of a patient cell proliferation (V2, V3) as well as by increasing the apoptotic with mycosis fungoides), SeAx and Hut 78 (both derived from peripheral rate (V3). Unbalanced expression of versican isoforms is described blood of a patient with SéS) were used. All cell lines were kindly 16 in pathological conditions, such as increased expression of V0 and provided by Dr Keld Kaltoft, Aahus, Denmark. Cell lines were grown in V1 in cancer.8 Moreover, existing literature suggests that versican supplemented RPMI 1640 medium (Invitrogen, Carlsbad, CA, USA). has the ability to regulate migratory behavior of inflammatory cells, including lymphocytes.8–10 Versican is therefore a recognized Gene expression profiling and data analysis cell fate and motility modulator that may facilitate tumor cell Total RNA, double-stranded cDNA and labeled complementary RNA were invasion and metastasis.11,12 generated as previously described.17 After purification, complementary 1Department of Dermatology, University Hospital Zurich, Zurich, Switzerland and 2Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland. Correspondence: Professor M Urosevic-Maiwald, Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, Zurich 8091, Switzerland. E-mail: [email protected] 3Current address: Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. 4Current address: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Penzberg, Penzberg, Germany. 5Current address: Division of Dermatology, National Hospital Organization Okayama Medical Center, Okayama, Japan. Received 14 January 2015; revised 13 March 2015; accepted 7 April 2015; accepted article preview online 27 April 2015; advance online publication, 15 May 2015 Versican upregulation in Sézary cells K Fujii et al 2025 RNA was hybridized to HG-U95Av2 GeneChip arrays (Affymetrix, Santa HotStart system in the LightCycler thermocycler (Roche Diagnostics). Clara, CA, USA). Chips were hybridized, washed and stained according to Versican V0–V3 primers were designed by us (Supplementary Table S1) protocols provided by Affymetrix. and synthetized by Microsynth (Balgach, Switzerland). Primers for versican The scaling, data normalization and polishing were performed according V0/1 and housekeeping genes were purchased from Search LC (Heidel- to the protocol previously described by us.17 Data analysis was carried berg, Germany). Platelet-derived growth factor (PDGF) 10 ng/ml (Gibco Life out with the GeneSpring Expression Analysis software (Silicon Genetics, Technologies, Carlsbad, CA, USA) was used for stimulation of VCAN Redwood City, CA, USA). Briefly, expression profiles of CD4+Vβ+ cells and expression during 48 h. CD4+Vβ − cells were compared using a non-parametric, Mann–Whitney test with Benjamini–Hochberg multiple-testing correction (Po0.005), fold- change cutoff ⩾ 1 and a detection call filter ⩾ 1 (at least one of the samples Western blotting in each group had to be called 'present'). Mining of functional gene Cells lysed with either TRIzol or RIPA lysis buffer were used for protein associations was performed using Cytoscape (http://www.cytoscape.org)18 analysis. Proteins were separated by sodium dodecyl sulfate- and GeneMANIA plug-in.19 Clustering analysis and display was performed polyacrylamide gel electrophoresis using the NuPAGE SDS-PAGE Gel with Gene Cluster and Tree View program, respectively (http://rana.lbl.gov). System (Invitrogen) on 10% Tris-glycine gels (Invitrogen) under reducing conditions according to the manufacturer’s instructions and transferred onto nitrocellulose membranes (Invitrogen). Versican V0/V1 antibody from Generation of versican V1 vector Dianova (ABR-27039, Hamburg, Germany) was diluted at 1:2000. In order to overexpress versican V1 in CTCL cell lines, we generated a lentiviral vector containing versican V1 (Supplementary Figure S1). Human fibroblasts (WH87) were stimulated by transforming growth factor (TGF)-β Assessment of cluster formation in V1-transfected CTCL cell lines to induce versican V1 expression. Following RNA extraction, mRNA Naive, control- and V1-transfected CTCL cell lines were washed and diluted fragments of V1 isoform were amplified, extracted and ligated, producing to 2 × 105/ml. After 24 h incubation, clusters of cells were evaluated by a coding sequence of 8224 base pairs, which was then cloned into phase-contrast microscopy at × 100 magnification and scanned. Diameters lentiviral pHIV-1 vector with blasticidin-resistance gene.20 To differentiate (pixel) of five clusters were measured using Adobe Photoshop CS5 (Adobe between endogenous and transduced versican V1, the vector was labeled Systems, San José, CA, USA). with VSV-G-tag. The same vector with green fluorescent protein instead of V1 was used as mock control (mRNA and protein expression data are Migration assay shown in Supplementary Figure S2). Cell migration was assayed with a modified Boyden chamber assay system. Transwells (BD, Franklin Lakes, NJ, USA) with polycarbonate membranes Real-time quantitative PCR
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