title: Interleukin-6 increases matrix metalloproteinase-14 (MMP-14) levels via down-regulation of p53 to drive cancer progression.
abstract: Matrix metalloproteinases (MMPs) play critical roles in cancer invasion and metastasis by digesting basement membrane and extracellular matrix (ECM). Much attention has focused on the enzymatic activities of MMPs; however, the regulatory mechanism of MMP expression remains elusive. By employing bioinformatics analysis, we identified a potential p53 response element within the MMP-14 promoter. Experimentally, we found that p53 can repress MMP-14 promoter activity, whereas deletion of this p53 response element abrogated this effect. Furthermore, we found that p53 expression decreases MMP-14 mRNA and protein levels and attenuates MMP-14-mediated cellular functions. Additional promoter analysis and chromatin immunoprecipitation studies identified a mechanism of regulation of MMP-14 expression by which p53 and transcription factor Sp1 competitively bind to the promoter. As the correlation between inflammation and cancer aggressiveness is well described, we next sought to evaluate if inflammatory cytokines could differentially affect p53 and MMP-14 levels. We demonstrate that interleukin-6 (IL-6) down-regulates p53 protein levels and thus results in a concomitant increase in MMP-14 expression, leading to enhanced cancer cell invasion and metastasis. Our data collectively indicate a novel mechanism of regulation of MMP-14 by a cascade of IL-6 and p53, demonstrating that the tumor microenvironment directly stimulates molecular changes in cancer cells to drive an invasive phenotype.
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY, USA.|Molecular and Cellular Pharmacology Program, Department of Pharmacology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Cathcart
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Banach
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, NY, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Goligorsky
authors.affiliation: Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016207:Cytokines; C508600:IL6 protein, human; D015850:Interleukin-6; D016329:Sp1 Transcription Factor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: IL-6; MMP-14; metastasis; p53