Modulation of the plasminogen activation system by inflammatory cytokines in human colon carcinoma cells

Trân-Thang, C; Kruithof, E.K.O.; Lahm, Hans‐Werner; Schuster, W-A; Tada, Mitsuhiro; Sordat, Bernard

doi:10.1038/bjc.1996.447

Cited by 34 publications

(21 citation statements)

References 51 publications

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“…Similar data are available for MMPs (26,27), whose control by genetic (29) and pharmacological means (30) has been shown to inhibit the aggressiveness of experimental melanoma. However, information on the control of these proteases by inflammatory cytokines in tumor cells is still limited, and an inconsistency in the trend is seen in the present information (31)(32)(33)(34)(35)(36)(37)(38).…”

Section: Introductionmentioning

confidence: 58%

Cytokine-dependent invasiveness in B16 murine melanoma cells: Role of uPA system and MMP-9

et al. 2006

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Abstract. Proteases are crucial for the spread of cancer cells from a primary tumor to the site of secondary growth. This study examined the ability of IFNÁ and TNF· to stimulate a better invasiveness in B16 murine melanoma cells, and investigated whether this enhanced ability was related to a higher expression of protease activities, such as urokinase plasminogen activator (uPA) and its receptor (uPAR), and matrix metalloproteinases 2 and 9 (MMP-2, MMP-9). We found that murine melanoma cells enhanced their lungcolonizing potential in vivo and invasiveness through Matrigel-coated filters upon costimulation with IFNÁ and TNF·; neither IFNÁ nor TNF· alone, at the dose used in the experiments, was able to elicit a change in the invasive/ metastatic efficiency of melanoma cells. The invasive phenotype of murine melanoma cells stimulated with IFNÁ and TNF· was characterized by an enhanced uPA/uPAR and MMP-9 expression: TNF· promoted MMP-9 mRNA expression and pro-MMP-9 protein secretion, and the costimulation with IFNÁ and TNF· was required to potentiate the expression of mRNA and protein for uPAR, and to induce a redistribution of uPA from the soluble to the cell bodyassociated form. Both monoclonal antibodies, anti-uPAR and anti-MMP-9, caused a significant reduction of invasiveness in IFNÁ/TNF·-stimulated melanoma cells. These results indicate that invasiveness in B16 murine melanoma cells can be regulated in a cytokine-specific fashion and is dependent on the synergism between the uPA/uPAR system and MMP-9.

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Section: Introductionmentioning

confidence: 58%

Cytokine-dependent invasiveness in B16 murine melanoma cells: Role of uPA system and MMP-9

et al. 2006

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“…For the hypoxic treatment, the cells were transferred to a combined workbench/incubator 20 with a humidified atmosphere of 1%, 2%, 3.5%, 5%, 6.5%, and 8% oxygen and 5% CO 2 balanced with N 2 and incubated at 37°C for up to 48 hours. After 1,2,4,8,12,16,24,32, 40, and 48 hours, the cell cultures were processed directly in the incubator. The control cultures maintained in 21% oxygen and 5% CO 2 were processed every 8 hours for the duration of the experiment.…”

Section: Hypoxic Treatmentmentioning

confidence: 99%

Identification of a tightly regulated hypoxia-response element in the promoter of human plasminogen activator inhibitor–1

Fink

Kazlauskas

Poellinger

et al. 2002

Blood

134

107

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Plasminogen activator inhibitor-1 (PAI-1) plays a key role in control of coagulation and tissue remodeling and has been shown to be regulated by a number of cell stimuli, among those hypoxia. In this study we characterize the hypoxia-mediated induction of PAI-1 in human hepatoma cell line HepG2. We found that PAI-1 is tightly regulated in a narrow oxygen gradient. After incubation at oxygen concentrations of 1% to 2%, a 60-fold increase in PAI-1 messenger RNA levels was observed, whereas mild hypoxic conditions of more than 3.5% did not appear to induce transcription. Moreover, increased levels of PAI-1 protein were observed after incubation at low oxygen tensions. Through sequence analysis, several putative hypoxia-response elements (HREs 1-5) were identified in the human PAI-I promoter. Reporter gene assays showed that the HRE-2 (؊194 to ؊187) was necessary and sufficient for the hypoxia-mediated response. By electrophoretic mobility assay we observed hypoxia-dependent binding of a protein complex to the HRE-2 motif. Further analysis demonstrated that HRE-2 was specifically recognized by the hypoxia-inducible transcription factor 1␣-arylhydrocarbon nuclear translocator complex. Taken IntroductionPlasminogen activator inhibitor-1 (PAI-1) plays a central role in the control of physiologically important mechanisms involved in the homeostasis of blood coagulation and remodeling of extracellular matrix (reviewed by Booth 1 ). The effect of PAI-1 is mediated through inhibition of urokinase and tissue type plasminogen activators. The importance of PAI-1 in the regulation of fibrinolytic activity is highlighted by several studies documenting an association between increased levels of PAI-1 and the risk of developing a cardiovascular disease. [2][3][4] Furthermore, numerous clinical studies of different types of cancer have identified high levels of plasma PAI-1 as a strong prognostic factor for more metastatic forms of cancer, concomitant with a poorer clinical outcome (reviewed by Harbeck et al 5 ).PAI-1 is produced by a variety of cell types in vitro, such as hepatocytes, 6 platelets, 7 smooth muscle cells, 8 and endothelial cells. 9 The sources of PAI-1 in vivo have not as yet been identified. However, studies in rabbits indicate that the liver and endothelial cells are the most important producers. 10 Several agents induce PAI-1 at the transcriptional level, including phorbol esters, 11 inflammatory cytokines, 12 transforming growth factor ␤, 13 and hypoxia. 14 For most of these stimuli, the signal transduction pathways have been identified, including target transcription factors and the corresponding specific transcriptional control elements within the regulated target genes. 15,16 Recently, it has been found that a 300-base pair stretch in the promoter region of the human PAI-1 gene is necessary for the responses to hypoxia and that these responses were mediated by the hypoxia-inducible transcription factor, HIF-1. 17,18 There is, however, no information available about molecular mechanisms involved in the cont...

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“…In an attempt to explore differentially-expressed genes in stomach cancer cells (NUGC-3) treated with growth factor, such as HGF, we found that IL-1β had a 3.26-fold upregulation using human cDNA microarrays. Although IL-1β-induced uPA regulation was similar to other studies (15,24), the mechanism by which the pathway appears to be the predominant pathway for uPA regulation was shown differently. Our results are consistent with the report showing that activation of p42/p44 MAPK is involved in the expression of uPA in different cell types (25,26).…”

Section: Discussionmentioning

confidence: 62%

“…Several lines of evidence have shown that the concentration of IL-1β in plasma of patients with lung cancer is significantly elevated (12) and is linked to the risk of lung cancer (13). Moreover, IL-1β has been reported to regulate uPA expression in various cancer cells (14,15). However, the mechanism by which IL-1β activates the metastatic phenotype in stomach cancer is unknown.…”

Section: Introductionmentioning

confidence: 99%

IL-1β-stimulated urokinase plasminogen activator expression through NF-κB in gastric cancer after HGF treatment

et al. 2014

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Abstract. The potential of hepatocyte growth factor (HGF) to regulate the expression of urokinase plasminogen activator (uPA) in a gastric cancer cell is not widely acknowledged. To identify the genes associated with the plasminogen activator proteolytic axis by HGF, we used cDNA microarray technology and selected genes upregulated or downregulated in two gastric cell lines (NUGC-3 and MKN-28). First, IL-1β RNA and protein were confirmed to be upregulated. Then, we investigated the effect of IL-1β induced by HGF on the uPA system, facilitating the migration and invasion of cancer cells in the metastatic process. The role for IL-1β in HGF-induced upregulation of uPA was determined by knockdown of IL-1β with IL-1β shRNA and a chromatin immune precipitation assay. The levels of IL-1β and uPA were upregulated in cells treated with HGF in a dose-dependent manner. HGF-induced upregulation of uPA was suppressed by IL-1β knockdown. HGF enhanced the binding activity of NF-κB to the uPA promoter in control cells, but not in the IL-1β shRNA cells. We confirmed the functional role of HGF inactivation of the uPA promoter by a reporter gene assay. Downregulation of IL-1β using IL-1β shRNA also decreased cell proliferation and in vitro cell invasion. IL-1β stimulated uPA expression through ERK and NF-κB in gastric cancer, which may therefore be promising targets for gastric cancer therapy.

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Modulation of the plasminogen activation system by inflammatory cytokines in human colon carcinoma cells

Cited by 34 publications

References 51 publications

Cytokine-dependent invasiveness in B16 murine melanoma cells: Role of uPA system and MMP-9

Cytokine-dependent invasiveness in B16 murine melanoma cells: Role of uPA system and MMP-9

Identification of a tightly regulated hypoxia-response element in the promoter of human plasminogen activator inhibitor–1

IL-1β-stimulated urokinase plasminogen activator expression through NF-κB in gastric cancer after HGF treatment

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