CCAAT Enhancer Binding Protein-β Regulates Matrix Metalloproteinase-1 Expression in Interleukin-1β–Stimulated A549 Lung Carcinoma Cells

Abstract

Matrix metalloproteinase-1 (MMP-1) is an inflammationinducible neutral protease that mediates extracellular matrix remodeling and promotes tumor invasion. In this study, we examined the activation of MMP-1 gene expression in A549 lung carcinoma cells stimulated with the inflammatory cytokine interleukin-1β (IL-1β). We found that MMP-1 mRNA levels were maximal following 16 hours of IL-1β stimulation and that this correlated with the expression of the transcription factor CCAAT enhancer-binding protein-β (CEBPB). Knockdown of CEBPB expression with short hairpin RNA abrogated the expression of MMP-1, MMP-3, and MMP-10 in IL-1β-stimulated A549 cells. An established CEBP element in the MMP-1 promoter was found to be required for basal and IL-1β-induced transcription. Electrophoresis mobility shift assays showed that CEBPB binds to this promoter element maximally 16 hours after IL-1β stimulation. DNA affinity chromatography studies showed that the LAP1, LAP2, and LIP isoforms of CEBPB bind to the IL-1β-responsive CEBPB site in the MMP-1 promoter. Exogenous expression of the LAP1 and LAP2 isoforms stimulated the MMP-1 promoter, whereas LIP had no effect. Phosphorylation of CEBPB at Thr 235 peaked at 16 hours in IL-1β-stimulated cells. The MEK inhibitor U0126 inhibited this phosphorylation and reduced MMP-1 gene induction. These studies establish CEBPB as an important mediator of metalloproteinase gene activation during inflammatory responses in lung cancer cells and highlight the different regulatory roles of CEBPB isoforms. (Mol Cancer Res 2009;7(9):1517-24)

The polymorphism rs944289 predisposes to papillary thyroid carcinoma through a large intergenic noncoding RNA gene of tumor suppressor type

“…It also has been described as a tumor suppressor in lung and liver tumors (39,40). The function of C/EBPβ in tumorigenesis is less investigated (41,42). Our findings show that both C/EBPα and C/EBPβ activate PTCSC3 promoter activity and that the risk allele significantly reduces the activity generated by p42 C/EBPα and C/EBPβ.…”

Epigenetic regulation of proMMP-1 expression in the HT1080 human fibrosarcoma cell line

“…In most tumor cells, proMMP-1 mRNA levels are very low but can be induced by a wide variety of stimuli (7,8,(26)(27)(28). For instance, interleukin-1β, UV radiations or phorbol esters, increase proMMP-1 gene expression through histone posttranslational modifications (22,29).…”

Role of matrix metalloproteinase-10 in the BMP-2 inducing osteoblastic differentiation

“…MMP-10, also called as stromelysin-2, initially identified in a human adenocarcinoma cDNA library, is demonstrated to be expressed in osteoblasts at sites of bone formation as well as in chondrocytes of the growth plate in neonatal ribs in human [11]. Inflammatory cytokine, such as interleukin-β, activates MMP-3 and MMP-10, and these MMPs are considered to expand the degradative potential of cancer cells by targeting no-collagen matrix proteins such as fibronectin and laminin as well as activating latent MMP-1 [12,13]. Moreover, MMP-10 is enhanced in patients with atherosclerosis and in pathological conditions with increased thrombin generation [14,15].…”