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Cyclophilin A-EMMPRIN Interaction Induces Invasion of Head and Neck Squamous Cell Carcinoma

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Cyclophilin A-EMMPRIN Interaction Induces Invasion of Head and Neck Squamous Cell Carcinoma 198 ONCOLOGY REPORTS 27: 198-203, 2012 Cyclophilin A-EMMPRIN interaction induces invasion of head and neck squamous cell carcinoma MASAFUMI TAKAHASHI, SHINSUKE SUZUKI and KAZUO ISHIKAWA Department of Otorhinolaryngology and Head and Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan Received July 11, 2011; Accepted August 10, 2011 DOI: 10.3892/or.2011.1474 Abstract. Extracellular matrix remodeling crucial to progression, the role of MMPs has been studied in malignant tumorigenesis involves proteolytic enzymes, primarily matrix tumors (1,2). In these tumors, MMP overexpression correlates metalloproteinases (MMPs). MMP production is stimulated with increased cancer invasiveness, both in vitro and in vivo by multiple factors, including the extracellular matrix metallo- and results in a poor prognosis (3). proteinase inducer EMMPRIN/CD147. Overexpression of A growing number of reports suggest that MMP expression EMMPRIN, a member of the immunoglobulin superfamily, in cancer tissue is promoted through soluble factors, such as cyto- promotes invasion, metastasis, growth and survival of malig- kines. In addition to several humoral factors, cell-cell interaction nant cells. Cyclophilin A (CypA) is a multifunctional protein mediated by cell adhesion molecules such as the extracellular that promotes cancer progression in various cancer types. CypA matrix metalloproteinase inducer EMMPRIN (also known as can interact with and activate EMMPRIN; however, the role of CD147) is important for MMP production in tumors (4-7). CypA-EMMPRIN interaction in oncogenicity is not completely EMMPRIN, a membrane glycoprotein greatly enriched understood. To investigate tumorigenicity induced by the on the surface of tumor cells (8-10), is known to stimulate CypA-EMMPRIN interaction, we stimulated EMMPRIN- increased MMP synthesis in tumor and neighboring stromal expressing head and neck squamous cell carcinoma (HNSCC) cells and promote tumor growth and lymphatic metastasis cells with CypA. The 3-(4,5-dimethylthiazol-2-yl)-2,5-di- (11,12). EMMPRIN is highly expressed in head and neck phenyltetrazolium bromide dye assay revealed that HNSCC squamous cell carcinoma (HNSCC) cells (13). We previously cell proliferation increased upon stimulation of the cells with showed that EMMPRIN plays an important role in HNSCC CypA, whereas cisplatin-induced cell death decreased after progression through MMP production and activation (14,15). stimulation. Gelatin zymography showed that CypA also Although increasing evidence implicates EMMPRIN in induced MMP-9 up-regulation. Moreover, HNSCC cell inva- cancer progression, the precise mechanisms of EMMPRIN sion through Matrigel™-coated membranes was increased upon activation remain unclear. Homophilic EMMPRIN- stimulation of cells with CypA. This elevated invasive potential EMMPRIN interaction has been proposed to be a mechanism was abrogated by an EMMPRIN function-blocking antibody. by which EMMPRIN could induce MMP production (7,16). These findings suggest that CypA, through its interaction with In addition to the homophilic binding of EMMPRIN, recent EMMPRIN, contributes to HNSCC tumorigenesis. studies reported that cyclophilin A (CypA) acts as a ligand for EMMPRIN (17,18). The importance of the CypA-EMMPRIN Introduction interaction has been reported in rheumatoid arthritis (19), foam cell formation (17) and also in several solid tumors (20-22). Matrix metalloproteinases (MMPs) are a subfamily of However, the role of CypA and its interaction with EMMPRIN endopeptidases, enzymes that degrade components of the in HNSCC has not yet been evaluated. extracellular matrix (ECM). Because disruption of ECM, In this study, we sought to investigate the functional role including the basement membrane, which serves as a barrier of CypA and its receptor EMMPRIN during the process of between tissue compartments, is a crucial step in tumor HNSCC progression in vitro. Using two HNSCC cell lines, we examined whether CypA induces tumorigenic behavior in HNSCC cells, such as cell proliferation, drug resistance and MMP expression. In addition, we evaluated CypA-induced HNSCC cell invasion, both with and without an EMMPRIN Correspondence to: Dr Shinsuke Suzuki, Department of Otorhino- laryngology and Head and Neck Surgery, Akita University Graduate function-blocking antibody, to confirm the role of the CypA- School of Medicine, Akita 010-8543, Japan EMMPRIN interaction in HNSCC progression. E-mail: [email protected] Materials and methods Key words: cyclophilin A, EMMPRIN, head and neck squamous cell carcinoma Cell lines and culture. FaDu, a human hypopharyngeal squamous cell carcinoma cell line, was a kind gift from the TAKAHASHI et al: INVASION OF HEAD AND NECK SQUAMOUS CELL CARCINOMA 199 Department of Cell Biology and Morphology, Akita University Graduate School of Medicine (Akita, Japan). SAS, a human tongue squamous cell carcinoma cell line, was purchased from the Cell Engineering Division of RIKEN BioResorce Center (Tsukuba, Japan). The cells were maintained in Dulbecco's modified Eagle's medium (DMEM; Gibco-Invitrogen, Grand Island, NY, USA) supplemented with 10% fetal bovine serum (FBS) in a humidified atmosphere containing 5% CO2 at 37˚C. For stimulation experiments, the FaDu and SAS cells were preincubated with serum-free DMEM and subsequently incubated with serum-free medium containing 400 ng/ml of Figure 1. EMMPRIN expression in HNSCC cells. EMMPRIN protein expres- sion was determined by immunoblotting in the HNSCC cell lines FaDu and CypA (Sigma-Aldrich, St. Louis, MO, USA). SAS. Both HNSCC cell lines showed high EMMPRIN protein expression. Antibodies. A goat anti-EMMPRIN antibody, H-200 (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA), was used for immunoblotting. A mouse anti-EMMPRIN function-blocking serum-free DMEM with or without 400 ng/ml CypA. This antibody, UM-8D6 (Research Diagnostics Inc., Flanders, NJ, was followed by detection of gelatinolytic activity in the condi- USA), was used for the inhibition studies; its blocking activity tioned media by gelatin zymography. Using a 7.5% separating has been described previously (12,23). gel containing 0.3 mg/ml gelatin, the conditioned medium was resolved by SDS-PAGE under non-reducing conditions. The Immunoblotting. The FaDu and SAS cells were lysed in deter- gels were washed twice in 2.5% (w/v) Triton X-100 for 30 min gent containing 1% NP-40, 150 mmol/l NaCl, 1 mmol/l EDTA, at room temperature to remove SDS and then incubated for 0.1 mmol/l phenylmethylsulfonyl fluoride, 1 µg/ml leupeptin 24 h at 37˚C in reaction buffer containing 50 mM Tris-HCl and 1 µg/ml aprotinin. Protein levels were then determined (pH 7.6), 5 mM CaCl2 and 2.5% Triton X-100. Subsequently, by the Bio-Rad protein assay method (Bio-Rad Laboratories). the gels were stained with 2.5% (w/v) Coomassie Brilliant Total protein (40 µg) was separated on 8% SDS-PAGE gels Blue R-250 in 30% (v/v) methanol and 10% (v/v) acetic acid. and transferred to nitrocellulose membranes using a semi-dry After destaining with 30% methanol and 10% acetic acid, transfer machine (Bio-Rad Laboratories). The membranes gelatinolytic activities on the gel were detected as clear bands were blocked with 5% skim milk/TBS with Tween-20 (TBS-T) on a blue background of undigested gelatin. for 1 h at room temperature and then incubated overnight at 4˚C with primary antibodies in 5% skim milk in TBS-T. After Matrigel invasion assay. Cell invasiveness was evaluated washing thrice with TBS-T, the membranes were incubated in vitro using Matrigel™-coated semipermeable, modified for 1 h with a horseradish peroxidase-conjugated secondary Boyden chamber inserts with a pore size of 8 µm (Becton- antibody (Bio-Rad Laboratories) in 5% skim milk in TBS-T. Dickinson/Biocoat). The FaDu and SAS cells (2.5x104) were The filters were rinsed thrice with TBS-T, and the blots were plated in the insert containing serum-free medium with developed using luminol (Santa Cruz Biotechnology Inc.) and or without 10 µg/ml of the EMMPRIN function-blocking visualized by autoradiography. antibody. The lower chamber contained DMEM plus 10% FBS with or without 400 ng/ml of CypA, which served as Proliferation assay. The FaDu and SAS cells were plated in trip- a chemoattractant. To control the effect of inhibitors on cell licate at a density of 2x104 per well and allowed to seed overnight growth, the cells were also plated in parallel in a 96-well plate in a 96-well plate. The cells were grown in serum-free DMEM under identical conditions. After 48 h of treatment at 37˚C in for 24 h prior to experimental treatments and then treated with a 5% CO2 incubator, the cells in the insert were removed by the control vehicle PBS or CypA (400 ng/ml) in serum-free wiping gently with a cotton swab. Cells on the reverse side of DMEM for 24 h. Metabolically active cells were labeled with the insert were fixed and stained with Diff-Quik® (Sysmex, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide Kobe, Japan), according to the manufacturer's instructions. (MTT) tetrazolium for 1 h and measured at 570 nm. Invading cells in four representative fields were counted by light microscopy at x200 magnification. Mean ± SE was Drug resistance assay. Drug resistance was determined by the calculated from three independent experiments. Metabolically MTT (Sigma-Aldrich) assay. Briefly, the FaDu and SAS cells active cells were identified by the MTT assay. The number of were plated in triplicate at a density of 2x104 per well and allowed invading cells was adjusted accordingly. to seed overnight in a 96-well plate. The cells were grown in serum-free DMEM for 24 h prior to experimental treatments and Statistical analysis. The Wilcoxon-Mann-Whitney two-tailed then treated with either the control vehicle DMSO or cisplatin exact test was used to assess the statistical significance of (0.5 µM) with or without CypA (400 ng/ml) in DMEM with 10% differences in proliferation, drug resistance, MMP-9 expres- FBS for 24 h.
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