title: S100A8/A9 regulates MMP-2 expression and invasion and migration by carcinoma cells.
abstract: Intracellular calprotectin (S100A8/A9) functions in the control of the cell cycle checkpoint at G2/M. Dysregulation of S100A8/A9 appears to cause loss of the checkpoint, which frequently characterizes head and neck squamous cell carcinoma (HNSCC). In the present study, we analyzed carcinoma cells for other S100A8/A9-directed changes in malignant phenotype. Using a S100A8/A9-negative human carcinoma cell line (KB), transfection to express S100A8 and S100A9 caused selective down-regulation of MMP-2 and inhibited in vitro invasion and migration. Conversely, silencing of endogenous S100A8 and S100A9 expression in TR146 cells, a well-differentiated HNSCC cell line, increased MMP-2 activity and in vitro invasion and migration. When MMP-2 expression was silenced, cells appeared to assume a less malignant phenotype. To more closely model the architecture of cell growth in vivo, cells were grown in a 3D collagen substrate, which was compared to 2D. Growth on 3D substrates caused greater MMP-2 expression. Whereas hypermethylation of CpG islands occurs frequently in HNSCC, S100A8/A9-dependent regulation of MMP-2 could not be explained by modification of the upstream promoters of MMP2 or TIMP2. Collectively, these results suggest that intracellular S100A8/A9 contributes to the cancer cell phenotype by modulating MMP-2 expression and activity to regulate cell migration and mobility.
authors.affiliation: Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Silva
authors.affiliation: Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Prokopios P
authors.initials: PP
authors.lastname: Argyris
authors.affiliation: Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Xianqiong
authors.initials: X
authors.lastname: Zou
authors.affiliation: Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA; Mucosal and Vaccine Research Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.
authors.forename: Karen F
authors.initials: KF
authors.lastname: Ross
authors.affiliation: Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA; Mucosal and Vaccine Research Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417, USA. Electronic address: mcherzb@umn.edu.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Herzberg
mesh_terms: D015153:Blotting, Western; D040501:Calgranulin A / Q000235:genetics* / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D003094:Collagen / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D003094:Collagen; D020778:Matrix Metalloproteinase 2
keywords: Calprotectin; Carcinoma; In vitro; Matrix metalloproteinase-2; S100A8/A9