Fibronectin Increases Matrix Metalloproteinase 9 Expression through Activation of c-Fos via Extracellular-regulated Kinase and Phosphatidylinositol 3-Kinase Pathways in Human Lung Carcinoma Cells

Abstract

Matrix metalloproteinases (MMPs) 2 are a family of zinc enzymes responsible for degradation of extracellular matrix components including basement membrane collagen, interstitial collagens, fibronectin (FN), and various proteoglycans during normal remodeling and repair processes (1, 2). The potent proteolytic activities of MMPs are mainly regulated by the concomitant expression of specific tissue inhibitors of matrix metalloproteinases (3). Excessive or inappropriate expression of MMPs may contribute to the pathogenesis of tissue destructive processes in a wide variety of diseases including lung disorders like bronchial asthma, chronic obstructive pulmonary disease, acute lung injury, pulmonary hypertension, and interstitial lung diseases (2, 4). In addition, MMPs have been implicated in the progression and metastases of different tumors including lung cancer (see later in text).One member of the MMP family is the 92-kDa type IV collagenase MMP-9. The MMP-9 gene is encoded on chromosome 20 and its expression is under the control of a 2.2-kb upstream regulatory sequence harboring binding sites for AP-1, NF-B, Sp1, and others (5). MMP-9 expression is increased in malignant cancers when compared with benign tumors and non-invasive ones, and there is compelling in vitro and in vivo evidence for a role of MMP-9 in tumor invasion and angiogenesis (6, 7). Its dramatic overexpression in cancer and various inflammatory conditions suggest that this protease is a potential target for the development of novel therapeutic interventions (8).Because of its perceived importance, our research focuses on the factors that increase MMP-9 expression in the lung. Our search led us to FN, a matrix glycoprotein highly expressed in tobacco-related lung disease that has been shown to stimulate lung carcinoma cell growth through several mechanisms (9 -11). Cell adhesion to FN results in MMP secretion in normal and tumor cell systems (12)(13)(14). These studies suggest that tumor cell interactions with FN might lead to MMP-9 expression thereby promoting cancer cell migration, invasion, and related processes. However, the mechanisms by which FN stim-* This work was supported by American Lung Association Bioresearch Grant RG-10215N (to S. W. H.) and by a Merit Review Grant from the Department of Veterans Affairs (to J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.

Extracellular Matrix Fibronectin Increases Prostaglandin E2 Receptor Subtype EP4 in Lung Carcinoma Cells through Multiple Signaling Pathways

“…There are a few studies that explore the transcriptional regulation of EP4 and transcription factor interactions in its promoter region. Studies show that a GC-rich/Sp1 binding site located within the first 80 bases of the transcription start site in the EP4 promoter region is important in transcription initiation of the EP4 gene (24), and several negative, positive and lipopolysaccharide/ serum-responsive regions are located at different areas in the mouse EP4 promoter (16). We confirmed that AP-2 sites were involved in Fn-induced EP4 gene expression using mutated EP4 constructs.…”

“…However, ERK played no role in the increase of EP4 expression induced by peroxisome proliferatoractivated receptor ␤/␦ activation (15), suggesting the existence of independent pathways that differ according to the stimulus. Fn activates MMP-9 via the ERK and PI3K/Akt signaling pathways in NSCLC and ovarian cancer cells (24,42,43). The inhibitor of PI3K, wortmannin, blocked the effect of Fn on stimulation of ERK phosphorylation, indicating cross-talk between the PI3K and ERK1/2 pathways in NSCLC cells.…”

“…In order to elucidate the mechanism(s) involved in Fn induction of EP4, we attempted to delineate the signaling pathways involved in induction of EP4 expression in lung carcinoma cells in response to Fn treatment. Data from our laboratory (4,21,24,39,40) and data of others (3,41) have demonstrated that adhesion to Fn activates several kinase signaling pathways, including ERK, PI3K, PKC, and PKA. We found that inhibitors of the PI3K kinase and ERK prevented Fn-induced EP4 protein expression, suggesting that the activation of these dual kinase signaling pathways is necessary for Fn-induced EP4 expression.…”

“…We previously demonstrated that Fn activated ERK and PI3K/Akt signaling pathways in NSCLC cells (4,23,24). Here, we examined if inhibition of these kinase signal pathways diminished or abrogated the effects of Fn on EP4.…”

Tumor Necrosis Factor-related Weak Inducer of Apoptosis Augments Matrix Metalloproteinase 9 (MMP-9) Production in Skeletal Muscle through the Activation of Nuclear Factor-κB-inducing Kinase and p38 Mitogen-activated Protein Kinase

“…3C, overexpression of either IB␣⌬N or TAM67 significantly blocked the TWEAKinduced activation of MMP-9 promoter in myotubes. We also studied the role of NF-B and AP-1 in TWEAK-induced expression of MMP-9 in myotubes using a reporter gene assay in which the conserved AP-1, NF-B, or SP-1 binding sites in the human MMP-9 gene promoter were mutated (30). TWEAK-induced activation of human MMP-9 promoter was significantly blocked by point mutations in either AP-1 or NF-B but not SP-1 binding site (Fig.…”