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Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP-9).

ABSTRACT: The transcription factor late SV40 factor (LSF) is overexpressed in human hepatocellular carcinoma (HCC) fostering a highly aggressive and metastatic phenotype. Angiogenesis is an essential component of cancer aggression and metastasis and HCC is a highly aggressive and angiogenic cancer. In the present studies, we analyzed the molecular mechanism of LSF-induced angiogenesis in HCC. Employing human umbilical vein endothelial cells (HUVEC) differentiation assay and chicken chorioallantoic membrane (CAM) assay we document that stable LSF overexpression augments and stable dominant negative inhibition of LSF (LSFdn) abrogates angiogenesis by human HCC cells. A quest for LSF-regulated factors contributing to angiogenesis, by chromatin immunoprecipitation-on-chip (ChIP-on-chip) assay, identified matrix metalloproteinase-9 (MMP-9) as a direct target of LSF. MMP-9 expression and enzymatic activity were higher in LSF-overexpressing cells and lower in LSFdn-expressing cells. Deletion mutation analysis identified the LSF-responsive regions in the MMP-9 promoter and ChIP assay confirmed LSF binding to the MMP-9 promoter. Inhibition of MMP-9 significantly abrogated LSF-induced angiogenesis as well as in vivo tumorigenesis, thus reinforcing the role of MMP-9 in facilitating LSF function. The present findings identify a novel target of LSF contributing to its oncogenic properties.

SUBMITTER: Santhekadur PK

PROVIDER: S-EPMC3270996 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Transcription factor Late SV40 Factor (LSF) functions as an oncogene in hepatocellular carcinoma.

Project description:Hepatocellular carcinoma (HCC) is a highly aggressive cancer with no currently available effective treatment. Understanding of the molecular mechanism of HCC development and progression is imperative for developing novel, effective, and targeted therapies for this lethal disease. In this article, we document that the cellular transcription factor Late SV40 Factor (LSF) plays an important role in HCC pathogenesis. LSF protein was significantly overexpressed in human HCC cells compared to normal hepatocytes. In 109 HCC patients, LSF protein was overexpressed in >90% cases, compared to normal liver, and LSF expression level showed significant correlation with the stages and grades of the disease. Forced overexpression of LSF in less aggressive HCC cells resulted in highly aggressive, angiogenic, and multiorgan metastatic tumors in nude mice. Conversely, inhibition of LSF significantly abrogated growth and metastasis of highly aggressive HCC cells in nude mice. Microarray studies revealed that as a transcription factor, LSF modulated specific genes regulating invasion, angiogenesis, chemoresistance, and senescence. The expression of osteopontin (OPN), a gene regulating every step in tumor progression and metastasis, was robustly up-regulated by LSF. It was documented that LSF transcriptionally up-regulates OPN, and loss-of-function studies demonstrated that OPN plays an important role in mediating the oncogenic functions of LSF. Together, these data establish a regulatory role of LSF in cancer, particularly HCC pathogenesis, and validate LSF as a viable target for therapeutic intervention.

| S-EPMC2889542 | biostudies-literature

Cytokines and signaling pathways regulating matrix metalloproteinase-9 (MMP-9) expression in corneal epithelial cells.

Project description:Matrix metalloproteinase-9 (MMP-9) is a well-known regulator and effecter of many cellular processes including wound healing. In the cornea, either too much or too little MMP-9 can be detrimental to overall wound repair. We investigated the secreted factors as well as the intracellular signaling pathways and the promoter sequences that mediate this regulation. Primary culture rabbit corneal epithelial cells were treated with various cytokines alone or in different combinations and MMP-9 induction was assessed by gel zymography. Pharmacological inhibitors were used to determine the intracellular signaling pathways induced by the cytokines tested and deletion promoter constructs were created to determine the regions of the MMP-9 promoter involved in the cytokine regulation, thereby assessing the exact transcription factors binding the MMP-9 promoter. We found that two cytokine families, transforming growth factor beta (TGF-beta) and interleukin 1 (IL-1), act additively in an isoform non-specific manner to induce MMP-9 in this cell type. Our data suggest TGF-beta mediated MMP-9 induction may be regulated by the NF-kappaB, Smad3, and JNK pathways, whereas the IL-1beta mediated induction may be regulated by the NF-kappaB and p38 pathways. Inhibition of the p38, NF-kappaB, or JNK pathways significantly reduced, but did not abrogate, basal MMP-9 levels. Inhibition of the ERK pathway did not have an effect on MMP-9 mediated expression in either the treated or untreated co-transfected cells.

| S-EPMC2990951 | biostudies-literature

Klotho Protein Reduced the Expression of Matrix Metalloproteinase-1 (MMP-1) and Matrix Metalloproteinase-3 (MMP-3) in Fibroblasts from Patients with Pelvic Organ Prolapse (POP) by Down-Regulating the Phosphorylation of ERK1/2.

Project description:BACKGROUND Pelvic organ prolapse (POP) is due to age-related atrophy and the weakening of the tissues of the pelvic floor, with degradation of collagen and extracellular matrix (ECM) by metalloproteinases (MMPs). This study aimed to investigates the role of the age-related enzyme klotho, encoded by the KL gene, in cultured fibroblasts obtained from patients with POP and the levels of reactive oxygen species (ROS), interleukin-6 (IL-6), and MMPs. MATERIAL AND METHODS Pelvic floor fibroblasts were obtained from connective tissue from three patients with POP and three normal subjects. Cell proliferation and ROS production were measured using a cell counting kit-8 (CCK-8) assay and flow cytometry. Levels of interleukin-6 (IL-6), klotho, metalloproteinase-1 (MMP-1), MMP-3, extracellular signal-regulated kinases 1/2 (ERK1/2), and p-ERK1/2 were measured by enzyme-linked immunoassay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot. RESULTS In cultured pelvic floor fibroblasts from patients with POP, the expression of klotho protein and klotho mRNA were significantly down-regulated in fibroblasts from patients with POP compared with normal fibroblasts. Klotho supplementation in cultured fibroblasts for patients with POP included increased cell growth, reduced expression of ROS reduction, and reduced the secretion of IL-6. Using qRT-PCR and Western blot, klotho supplementation of fibroblasts from patients with POP increased cell growth and reduced the levels of IL-6 and ROS in a dose-dependent way. CONCLUSIONS Klotho protein reduced the expression of MMP-1 and MMP-3 in fibroblasts from patients with POP by down-regulating the phosphorylation of ERK1/2.

| S-EPMC6542300 | biostudies-literature

"Splitting the matrix": intussusceptive angiogenesis meets MT1-MMP.

Project description:Pathological angiogenesis contributes to tumour progression as well as to chronic inflammatory diseases. In this issue of EMBO Molecular Medicine, Esteban and co-workers identify endothelial cell MT1-MMP as a key regulator of intussusceptive angiogenesis (IA) in inflammatory colitis. Thrombospondin 1 (TSP1) cleavage by MT1-MMP results in the binding of the c-terminal fragment of TSP1 to ?v?3 integrin, which induces nitric oxide (NO) production, vasodilation and further initiation of IA. This novel control mechanism of inflammatory IA points towards promising new therapeutic targets for inflammatory bowel disease.

| S-EPMC7005529 | biostudies-literature

No association between matrix metalloproteinase (MMP)-1, MMP-3, and MMP-7 SNPs and endometrial cancer risk.

Project description: Not available

| S-EPMC2770800 | biostudies-literature

Matrix Metalloproteinase-9 (MMP-9) Gene Polymorphism in Stroke Patients.

Project description:Matrix metalloproteinases (MMPs), endopeptidases degrading extracellular matrix, play an important role in the pathogenesis of atherosclerosis and vascular disease. The aim of this study was to evaluate the association between the C(-1562)T functional polymorphism in the MMP-9 gene and risk of stroke. We examined 322 patients with stroke and 410 controls. In the patient group, 52 % had type 2 diabetes. All subjects were genotyped for the C(-1562)T polymorphism by polymerase chain reaction and restriction analysis. A significant increase in T allele and CT + TT genotype frequencies was observed in patients compared with controls (OR 1.73, 95 % CI 1.34-2.23 and 1.89, 95 % CI 1.39-2.56, respectively). The T allele carriers were younger at the onset of stroke (63.5 ± 11.7 years) than patients with CC genotype (71 ± 14.1 years) (p = 0.0002). The comparison between patients with T2DM and without it showed that the T allele and CT + TT genotype were more frequent in T2DM patients (OR 1.48, 95 % CI 1.03-2.12 for T allele and 1.44, 95 % CI 1.93-2.24 for CT + TT genotype). In conclusion, our findings suggest that MMP-9 C(-1562)T polymorphism is significantly associated with risk of stroke in patients with and without T2DM.

| S-EPMC4643105 | biostudies-literature

Interdomain flexibility in full-length matrix metalloproteinase-1 (MMP-1).

Project description:The presence of extensive reciprocal conformational freedom between the catalytic and the hemopexin-like domains of full-length matrix metalloproteinase-1 (MMP-1) is demonstrated by NMR and small angle x-ray scattering experiments. This finding is discussed in relation to the essentiality of the hemopexin-like domain for the collagenolytic activity of MMP-1. The conformational freedom experienced by the present system, having the shortest linker between the two domains, when compared with similar findings on MMP-12 and MMP-9 having longer and the longest linker within the family, respectively, suggests this type of conformational freedom to be a general property of all MMPs.

| S-EPMC2676012 | biostudies-literature

Novel Matrix Metalloproteinase-9 (MMP-9) Inhibitors in Cancer Treatment.

Project description:Matrix metalloproteinases (MMPs) belong to a family of zinc-dependent proteolytic metalloenzymes. MMP-9, a member of the gelatinase B family, is characterized as one of the most intricate MMPs. The crucial involvement of MMP-9 in extracellular matrix (ECM) remodeling underscores its significant correlation with each stage of cancer pathogenesis and progression. The design and synthesis of MMP-9 inhibitors is a potentially attractive research area. Unfortunately, to date, there is no effective MMP-9 inhibitor that passes the clinical trials and is approved by the FDA. This review primarily focuses on exploring the diverse strategies employed in the design and advancement of MMP-9 inhibitors, along with their anticancer effects and selectivity. To illuminate the essential structural characteristics necessary for the future design of novel MMP-9 inhibitors, the current narrative review highlights several recently discovered MMP-9 inhibitors exhibiting notable selectivity and potency.

| S-EPMC10418771 | biostudies-literature

Matrix metalloproteinase-3 (MMP-3)–mediated gene therapy for glaucoma

Project description:Approximately 80 million people globally are affected by glaucoma, with a projected increase to over 110 million by 2040. Substantial issues surrounding patient compliance remain with topical eye drops, and up to 10% of patients become treatment resistant, putting them at risk of permanent vision loss. The major risk factor for glaucoma is elevated intraocular pressure, which is regulated by the balance between the secretion of aqueous humor and the resistance to its flow across the conventional outflow pathway. Here, we show that adeno-associated virus 9 (AAV9)–mediated expression of matrix metalloproteinase-3 (MMP-3) can increase outflow in two murine models of glaucoma and in nonhuman primates. We show that long-term AAV9 transduction of the corneal endothelium in the nonhuman primate is safe and well tolerated. Last, MMP-3 increases outflow in donor human eyes. Collectively, our data suggest that glaucoma can be readily treated with gene therapy–based methods, paving the way for deployment in clinical trials. Adeno-associated virus (AAV) vectors deliver MMP3 for the treatment of glaucoma.

| S-EPMC10115410 | biostudies-literature

Matrix metalloproteinase (MMP)-19-deficient fibroblasts display a profibrotic phenotype.

Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal interstitial lung disease of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/myofibroblastic foci are responsible for the excessive extracellular matrix (ECM) production and abnormal lung remodeling. We have recently found that matrix metalloproteinase 19 (MMP-19)-deficient (Mmp19-/-) mice develop an exaggerated bleomycin-induced lung fibrosis, but the mechanisms are unclear. In this study, we explored the effect of MMP-19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of Mmp19-/- lung fibroblasts revealed the dysregulation of several profibrotic pathways, including ECM formation, migration, proliferation, and autophagy. Functional studies confirmed these findings. Compared with wild-type mice, Mmp19-/- lung fibroblasts showed increased α1 (I) collagen gene and collagen protein production at baseline and after transforming growth factor-β treatment and increased smooth muscle-α actin expression (P < 0.05). Likewise, Mmp19-deficient lung fibroblasts showed a significant increase in proliferation (P < 0.01) and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel (P < 0.05). These findings suggest that, in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation, and in migration and proliferation.

| S-EPMC5243210 | biostudies-literature

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