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

Gene regulation and systems biology Pub Date : 2017-06-08 eCollection Date: 2017-01-01 DOI:10.1177/1177625017713996
Samuel Sheehy, Borhane Annabi
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引用次数: 7

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.

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膜1型基质金属蛋白酶在致癌炎性小体基因表达中的转录调控作用。
细胞膜1型基质金属蛋白酶(MT1-MMP)胞质结构域驱动的信号转导功能被认为调节许多炎症相关的癌细胞功能,包括迁移、增殖和存活。除了炎症生物标志物环氧化酶-2 (COX-2)表达上调外,MT1-MMP在传递细胞外促炎线索触发的细胞内信号中的作用仍然知之甚少。在这里,我们用phorpol -12-肉豆蔻酸-13-乙酸酯(PMA)触发HT1080纤维肉瘤细胞的炎症,PMA是COX-2和MT1-MMP的诱诱剂。为了评估MT1-MMP可能对炎症生物标志物发挥的全局转录调控作用,我们将基因阵列筛选与MT1-MMP基因瞬时沉默策略相结合。研究发现,在pma处理的细胞中,MT1-MMP的表达对几种炎症小体相关的生物标志物(如白细胞介素(IL)-1B、IL-6、IL- 12a和IL-33)以及转录因子(如EGR1、ELK1和ETS1/2)发挥刺激和抑制的转录控制作用。在所探索的信号转导途径中,MT1-MMP的沉默阻止了PMA磷酸化细胞外信号调节激酶、κB抑制剂和p105核因子κB (NF-κB)中间体。我们还发现了一个连接MT1-MMP和MMP-9转录调控的信号轴。总之,我们的数据表明MT1-MMP在炎症生物标志物的转录调节中有重要的参与,巩固了它在信号转导功能中的贡献,以及它的经典水解活性。
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