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.

BACKGROUND : Signal transducing functions driven by the cytoplasmic domain of membrane type-1 matrix metalloproteinase (MT1-MMP) are believed to regulate many inflammation-mediated cancer cell functions including migration, proliferation, and survival. Besides the upregulation of the inflammation biomarker cyclooxygenase (COX)-2 expression, MT1-MMP’s role in relaying the signals triggered from pro-inflammatory cues remain poorly understood. METHODS : Here, we treated HT1080 fibrosarcoma cells with phorbol-12-myristate-13-acetate (PMA), a well-known carcinogen and inducer of COX-2 and of MT1-MMP. In order to assess the global transcriptional regulatory role that MT1-MMP may exert on inflammation biomarkers, we combined gene array screens to transiant MT1-MMP gene silencing strategy. RESULTS : We found that MT1-MMP expression exerted both stimulatory and repressive transcriptional control of several inflammasome-related biomarkers such as 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, silencing of MT1-MMP prevented PMA from phosphorylating Erk, IκB, and p105 KF-κB intermediates. We also highlight a signaling axis linking MT1-MMP to MMP-9 transcriptional regulation. CONCLUSIONS : Altogether, our data evidence an important involvement of MT1-MMP in the transcriptional regulation of inflammatory biomarkers consolidating its contribution in signal transducing functions, in addition to its classical hydrolytic activity. Citation Format: Samuel Sheehy, Borhane Annabi. A role for the membrane type-1 matrix metalloproteinase in the transcriptional regulation of carcinogen-induced inflammasome components [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2697. doi:10.1158/1538-7445.AM2017-2697