Oncotarget

Research Papers:

Interleukin-6 increases matrix metalloproteinase-14 (MMP-14) levels via down-regulation of p53 to drive cancer progression

Jillian M. Cathcart, Anna Banach, Alice Liu, Jun Chen, Michael Goligorsky and Jian Cao _

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Oncotarget. 2016; 7:61107-61120. https://doi.org/10.18632/oncotarget.11243

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Abstract

Jillian M. Cathcart1,2, Anna Banach1, Alice Liu1, Jun Chen3, Michael Goligorsky3, Jian Cao1

1Division of Cancer Prevention, Department of Medicine, Stony Brook University, Stony Brook, NY, USA

2Molecular and Cellular Pharmacology Program, Department of Pharmacology, Stony Brook University, Stony Brook, NY, USA

3Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, NY, USA

Correspondence to:

Jian Cao, email: [email protected]

Keywords: MMP-14, IL-6, metastasis, p53

Received: June 11, 2016     Accepted: July 20, 2016     Published: August 12, 2016

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.


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