A Transcriptional Regulatory Role for the Membrane Type-1 Matrix Metalloproteinase in Carcinogen-Induced Inflammasome Gene Expression

Abstract

Signal-transducing functions driven by the cytoplasmic domain of membrane type-1 matrix metalloproteinase (MT1-MMP) are believed to regulate many inflammation-associated cancer cell functions including migration, proliferation, and survival. Aside from upregulation of the inflammation biomarker cyclooxygenase-2 (COX-2) expression, MT1-MMP’s role in relaying intracellular signals triggered by extracellular pro-inflammatory cues remains poorly understood. Here, we triggered inflammation in HT1080 fibrosarcoma cells with phorbol-12-myristate-13-acetate (PMA), an inducer of COX-2 and of MT1-MMP. To assess the global transcriptional regulatory role that MT1-MMP may exert on inflammation biomarkers, we combined gene array screens with a transient MT1-MMP gene silencing strategy. Expression of MT1-MMP was found to exert both stimulatory and repressive transcriptional control of several inflammasome-related biomarkers such as interleukin (IL)-1B, IL-6, IL-12A, and IL-33, as well as of transcription factors such as EGR1, ELK1, and ETS1/2 in PMA-treated cells. Among the signal-transducing pathways explored, the silencing of MT1-MMP prevented PMA from phosphorylating extracellular signal–regulated kinase, inhibitor of κB, and p105 nuclear factor κB (NF-κB) intermediates. We also found a signaling axis linking MT1-MMP to MMP-9 transcriptional regulation. Altogether, our data indicate a significant involvement of MT1-MMP in the transcriptional regulation of inflammatory biomarkers consolidating its contribution to signal transduction functions in addition to its classical hydrolytic activity.

MT1-MMP Cooperates with TGF-β Receptor-Mediated Signaling to Trigger SNAIL and Induce Epithelial-to-Mesenchymal-like Transition in U87 Glioblastoma Cells

“…In summary, a cooperative signal transducing role for MT1-MMP was previously documented to take part in the transcriptional control of inflammasome-related genes [ 25 ], autophagy [ 24 ], and COX-2 induction [ 35 ]. Here, we now provide the first evidence for a cooperative crosstalk linking TGF-β receptor-mediated signaling to that of MT1-MMP, both activities of which have also been occurring in CSC [ 65 , 66 , 67 ].…”

“…Among specific brain cancer biomarkers promoting invasion and metastasis and characterized by both matrix metalloproteinase (MMP) catalytic functions and intracellular signaling properties, membrane type-1 matrix metalloproteinase (MT1-MMP), a key membrane-bound MMP, is involved in extracellular matrix (ECM) degradation [ 19 , 20 , 21 ] and, more recently, signal transducing functions leading to angiogenesis [ 22 ], autophagy [ 23 , 24 ], inflammation [ 25 , 26 ], immune response [ 27 ], and cell death processes [ 28 , 29 ]. Interestingly, type I collagen, a major MT1-MMP substrate in the ECM, is a powerful inducer of cell-surface MT1-MMP expression through TGF-β–Smad signaling [ 26 , 30 , 31 ].…”

The Expanding Role of MT1-MMP in Cancer Progression

“…MT1-MMP regulated the transcription of dickkopf-related protein 3 (DKK3) in urothelial cells and Smad1 in several tumor cell lines [132]. In phorbol-12-myristate-13-acetate (PMA)-stimulated HT1080 cells, the expression of MT1-MMP modulated inflammasome gene expression [134]. The transcription of IL-33 and IL-12A was MT1-MMP-dependent [134].…”

“…In phorbol-12-myristate-13-acetate (PMA)-stimulated HT1080 cells, the expression of MT1-MMP modulated inflammasome gene expression [134]. The transcription of IL-33 and IL-12A was MT1-MMP-dependent [134]. MT1-MMP was found to translocate to the nucleus, where it induced the expression and activation of the phosphoinositide 3-kinase δ/Akt/GSK3β signaling cascade [135].…”

Invadopodia: clearing the way for cancer cell invasion

“…It was shown that the silencing of MT1-MMP gene expression resulted in reduced activation of phorbol-12-myristate-13-acetate (PMA)-induced transcription factors such as ELK1, EGR1, ETS1, and ETS2, caused by dysregulation of the phosphorylation of NF-κB/p105. Similarly, mutations within the cytoplasmic domain of MT1-MMP altered RhoA/ROK expression or RhoA-dependent shedding of CD44, and changed the phosphorylation status of Erk1/2, STAT3, and Akt in various type of cancer cells (77). In addition to proteolytic functions, MT1-MMP was described to control cell migration also through non-proteolytic mechanisms.…”