• Biomolecules & Therapeutics
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• v.10 no.4
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• pp.240-245
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• 2002

Cancer metastasis represents the most important cause of cancer death and antitumor agents that may inhibit this process have been extensively pursued. Invasion and metastasis of malignantly transformed cells involve degradation of the extracellular matrix (ECM) components by matrix metalloproteinases (MMP), especially MMP-2 and -9. We previously showed that H-ras-induced invasive phenotype may involve MMP-2, rather than MMP-9, in MCF10A cells. In the present study, we investigated the chemopreventive effect of Aster, a widely used culinary vegetable in Korea. We screened twelve extracts from three Aster species (Aster scaber, Aster oharai and Aster glehni) for the inhibitory effect on MMP activities of H-ras MCF10A human breast epithelial cells. All of the extracts tested in this study efficiently inhibited the gelatinolytic activities of MMP-2 and MMP-9. A more prominent inhibition was observed in MMP-2 activity compared to MMP-9. Out of twelve extracts, eight extracts showed>90％ inhibition of MMP-2 activity in H-ras MCF10A cells while only one extract showed>90％ inhibition of MMP-9 activity. We selected three extracts (AO-3, AG-3 and AS-EA) for further studies since they exerted a marked inhibition in the ratio of MMP-2 to MMP-9. Treatment with AO-3, AG-3 and AS-EA in H-ras MCF10A cells caused a significant inhibition of invasive phenotype and migration, proving a chemopreventive potential of these extracts. Taken together, our results demonstrate that extracts of Aster effectively inhibit invasion and migration of highly malignant human breast cells, possibly via downregulation of MMP-2 and MMP-9.

• Development and Reproduction
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• v.4 no.1
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• pp.45-52
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• 2000

Membrane type matrix metalloproteinases(MT-MMPs) have been suggested to play an important role during structural remodeling of various tissue. Expression patterns of MT1-MMP and MT2-MMP mRNAs were investigated in oocytes, embryos, ovary and oviduct of mouse during their differentiation or periovulatory period using RT-PCR technique. Both cDNA products of MT1- and MT2-MMP of immature oocytes were barely discernable with a minimum amount but the expressions were distinct in mature oocytes regardless that they were matured in vivo or in vitro. MT2-MMP was not expressed by 2-cell embryos but was expressed by 4-cell stage embryos. From the morula stage untill hatched blastocyst stage, embyos showed intesnse expression of MT2-MMP with a sudden increase at blastocyst stage. While mouse ovarian tissues showed both expression of MT1- and MT2-MMP, there was no stage-specific difference throughout the estrous cycle. Mouse oviducts also exhibit constant amount of both MT1- and MT2-MMP expressions throughout periovulatory period, i.e., before or after ovulation. These observations lead to suggest that the differential expressions of maternal MT1- and MT2-MMP during meiotic resumption of mouse oocytes and embryonic expression of MT2-MMP particularly at blastocyst stage might play a role in the differentiation of mouse oocytes and／or embryos. The precise function of MT1- and MT2-MMP with regards to their participation in the remodeling of ovarian and oviductal tissues remains in a question.

• Tuberculosis and Respiratory Diseases
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• v.52 no.5
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• pp.453-462
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• 2002

Background : Matrix metalloproteinases(MMPs) are a large family of proteolytic enzymes, which are involved in the degradation of many different components of the extracellular matrix. There is increasing evidence indicating that individual MMPs have important roles in tumor invasion by inactivating the MMPs. In this study, the correlation between MMPs and TIMPs expression, and the clinical outcome was investigated. Materials and Methods : Immunohistochemical staining of MMP-2, 9 and TIMP-1,2 were performed on paraffin-embedded tumor sections from 74 resected primary non-small cell lung cancers. Results : In 74 patients, MMP-2, MMP-9, TIMP-1, and TIMP-2 immunoreactivity was demonstrated in 24(34%), 19(26%) and 32(43%) of the paraffin-embedded tumors, respectively. The median survival of the MMP-2 positive cases was significantly shorter than that of the negative cases(20 vs 34 months). The median survival of the TIMP-2 positive cases was also was significantly longer than that of the negative cases (34 vs 18 months). The MMP-2, and MMP-9 expression level had a positively correlation with a more advanced stage and lymph node metastasis. There was inverse correlation between TIMP-2 expression and tumor invasion. The median survival of the MMP-2 negative/TIMP-2 positive cases was higher than that of the other cases. Conclusion : These results suggest that tumor invasion and lymph node metastasis are closely related to MMP-2 and MMP-9 expression. There was an inverse correlation between TIMP-2 and MMP-9 expression, and tumor invasion.

• Journal of Periodontal and Implant Science
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• v.35 no.3
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• pp.661-674
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• 2005

The purpose of this study was to quantify and compare the level of MMP-2, MMP-8 in the healthy, inflammed gingival tissue and inflammed gingival tissue associated with type 2 DM. We investigate whether expression of MMP-2, MMP-8 is increased by chronic periodontitis associated with type 2 DM. Gingival tissue samples were obtained during periodontal surgery or tooth extraction. Based on patient's systemic condition & clinical criteria of gingiva, each gingival samples were divided into three groups. Group l(n=8) is clinically healthy gingiva without bleeding and no evidence of bone resorption or periodontal pockets, obtained from 8 systemically healthy patients. Group 2(n=8) is inflammed gingiva from patients with chronic periodontitis. Group 3(n=8) is inflammed gingiva from type 2 diabetic patients with chronic periodontitis. Tissue samples were prepared and analyzed by Western blotting. The quantification of MMP-2, MMP-8 was performed using a densitometer and statistically analyzed by ANOVA. MMP-2, MMP-8 was expressed in all samples including healthy gingiva and increased in group 3 compared to group 1 and 2, and showed that significant variation was observed between group 1 & 3 in MMP-8 results. In conclusion, this study demonstrated that human gingival tissue with chronic periodontitis associated to type 2 diabetes showed slightly elevated MMP-2, MMP-8 levels compared to healthy gingiva and non-diabetic inflamed gingiva.

• BMB Reports
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• v.29 no.5
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• pp.484-487
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• 1996

The matrix metalloproteinases (MMPs) are members of a unique family of proteolytic enzymes that degrade components of the extracellular matrix. Significant evidence has accumulated to directly implicate members of the MMPs in tumor invasion and metastasis formation. To investigate the correlation between ras oncogene and MMP gene expression in various tumor cells, we detected mRNAs for the ras, MMP-2 and MMP-9 (72 kD and 92 kD type IV collagenases, respectively) genes in nine human tumor cell lines. The ras gene was expressed in seven cell lines; MMP-2 in three; MMP-9 in two cell lines tested. There was no direct correlation between the ras oncogene and MMP expression. A clear difference in the mRNA expression between MMP-2 and MMP-9 was observed among the cell lines. As an approach to study the effect of the ras oncogene on metastasis, we examined the expressions of MMP-2 and MMP-9 in HT1080 cells transfected with the v-H-ras gene. MMP-9 expression was Significantly enhanced in the ras-transfected HT1080 cells compared with the nontransfectants while ras transfection did not affect the expression of MMP-2. These results suggest the possible inducing effect of the ras oncogene on the metastasis by activation of the MMP-9 gene in HT1080.

• Archives of Pharmacal Research
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• v.28 no.11
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• pp.1257-1262
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• 2005

MMP-9 is a metalloproteinase capable of basement membrane degradation in vivo. Expression of MMP-9 can be found in normal conditions such as trophoblasts, osteoclasts, and leukocytes and their precursors. They also occur as well as in pathological conditions, such as the invasive growth of primary tumors, metastasis, angiogenesis, rheumatoid arthritis, and periodontal diseases. MMP-9 upregulation can be highly induced by a wide range of agents. These agents include growth factors, cytokines, cell-cell, and cell-ECM adhesion molecules, and agents altering cell shape. Here, we observed that TNF-$\alpha$ stimulated human monocytic cell line, HL-60 produced MMP-9 in a dose and time dependent manner. Real time PCR results indicated transcriptional upregulation of MMP-9 as early as 3 h post TNF-$\alpha$ stimulation. To investigate the signaling pathway underlined in TNF-$\alpha$ induced MMP-9 expression, three MAP kinase inhibitors were added to cells 1 h prior to TNF-$\alpha$ treatment. The ERK inhibitor completely abolished MMP-9 expression by TNF-$\alpha$. But neither p38 MAP kinase nor JNK inhibitor had an effect on TNF-$\alpha$ induced MMP-9 expression, suggesting that ERK activation is required for the MMP-9 induction by TNF-$\alpha$. Taken together, we found that TNF-$\alpha$ stimulation facilitates ERK activation, which results in the transcriptional upregulation of MMP-9 gene and subsequent MMP-9 production and secretion.

• Journal of Chest Surgery
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• v.40 no.5 s.274
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• pp.329-340
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• 2007

Background: Matrix Metalloproteinase (MMP) inhibition has emerged as a potential therapeutic strategy for the left ventricular dilatation that occurs after myocardial infarction. This study is designed to evaluate which treatment is better for attenuating the left ventricular remodeling via MMP inhibition 1) during the early, short highly MMP producing period of the initial phase or 2) during most of the period of the initial phase after myocardial infarction. Material and Method: Myocardial infarction was induced by ligation of the left anterior descending coronary artery in rabbits. The experimental group was divided into 3 groups. The myocardial infarction only (MI only) group consisted of 7 cases. The MMP inhibitor administered for 5 days after MI (MMPI 50) group had 6 cases, and these rabbits were given MMP inhibitor for 5 days after myocardial infarction, beginning with the postoperative first day. MMP inhibitor administered for 9 days (MMPI 90) group consisted of 5 cases and these rabbits were given MMPI for 9 days the same manner as above. CG2300 was used as a selective MMPI; this is a potent MMP-2 and -9 inhibitor Two-D echocardiograms were performed on all the groups at the time of preoperative period, the post-operative 1st week, the postoperative 20 week and the postoperative 30 week, and we measured the end-diastolic dimension (EDD), the end-systolic dimension (ESD), and the ejection fraction (EF). Result: The echocardiograms generally showed postoperative left ventricular dilatation in the MI only group. The EDD was increased significantly higher in the postoperative 1 week compared to the preoperative value (p<0.05). The ESD was also increased significantly higher in the postoperative 1st week, the postoperative 20 week and the postoperative 30 week compared to the preoperative value (p<0.05). Left ventricular dilatation was noted to be less In the MMPI 9d group than in the MI only and MMPI 5d groups. In the MMPI 9d group, there was no significant change of EF postoperatively compared to the preoperative period. MMP-2 and MMP-9 were measured from the infarcted myocardial tissue at post-MI 4 weeks by performing western blotting and zymography. The changes the of protein expression and activity of MMP-2 and MMP-9 were not significant in the three MI groups and the normal heart group. Histopathologic examination revealed severe collagen deposition in the MI only group. Collagen accumulation was reduced in both the MMPI groups. The MMPI 9d group revealed an increased number of capillaries. Conclusion: Left ventricular dilatation developed rapidly after, MI from ligation of the coronary artery and MMPI attenuated the ventricular dilatation. The effect of MMPI seemed to have better a result from its usage during most of the period of the initial phase after myocardial infarction. This suggested that increased neovascularization by MMPI may also contribute to attenuation of the left ventricular remodeling.

• Journal of Life Science
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• v.20 no.2
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• pp.275-280
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• 2010

Sulforaphane is a naturally occurring member of the iosothiocyanate family, which reveals chemopreventive capacities including anti-cancer, anti-inflammation and inhibition of MMP-9 activities. In this study, we investigated the effect of sulforaphane on the expression of matrix metalloproteinase-9 (MMP-9) in lipopolysaccharide (LPS)-induced Raw 264.7 cells. Sulforaphane strikingly suppressed the LPS-induced MMP-9 activity and mRNA expression in a dose-dependent manner. In addition, sulforaphane inhibited not only the LPS-induced MMP-9 promoter activity but also LPS-mediated activator protein-1 (AP-1) and nuclear factor-kB (NF-${\kappa}B$) promoter activity. Transient transfection by MMP-9 constructs, in which specific transcriptional factors were mutagenized, indicated that the effects of LPS and sulforaphane were mediated via AP-1 and NF-${\kappa}B$ response elements. We found that sulforaphane had the ability to suppress LPS-induced invasion in vitro. Taken together, these results demonstrated that sulforaphane effectively suppressed LPS-induced MMP-9 expression via modulation of promoter elements (AP-1 and NF-${\kappa}B$) in MMP-9 transcriptional activation.

• Reproductive and Developmental Biology
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• v.34 no.1
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• pp.55-62
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• 2010

Matrix metalloproteinases (MMP) play important roles in extracellular matrix (ECM) remodeling during ovarian follicular development, oocytes development and ovulation. In an attempt to investigate the effect of MMP activation in development cumulus-oocytes complexes, we examined the localization and expression of MMP, and monitored MMP expression profile. Cumulus-oocytes complexes were collected and matured in vitro for 24 hr, 36 hr and 48 hr. A mRNA expression of MMP-2, MMP-9, TIMP-2 and TIMP-3 was detected in all culture medium regardless of CC, DC and CDCs. Activity of MMP-2 in the DC progressively was increased from 24 hr to 48 hr. But MMP-9 was not detected in all culture medium. The localization of MMP-2 was also measured by immunohistochemistry analysis. The MMP-2 and TIMP-2 was detected in cumulus cell and oocyte zone pellucida. Expression of MMP-2 protein in the COCs was progressively increased from 24 hr to 48 hr. However, MMP-9 protein was progressively decreased from 24 hr to 48 hr. And TIMP-2 protein was most highly expressed in the CDCs 36 hr. Expression of TIMP-3 protein in the CDCs was progressively increased from 24 hr to 48 hr. In conclusion, these results suggest that MMP-2 plays a role in maintaining normal maturation and development by controlling the ECM inhibitor concentration on cumulus cell and oocytes.

• Biomedical Science Letters
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• v.18 no.2
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• pp.104-111
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• 2012

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which degrade extracellular matrix (ECM) during embryogenesis, wound healing, and tissue remodeling. Dysregulation of MMP activity is also associated with various pathological inflammatory conditions. In this study, we examined the expression pattern of MMPs during PMA-induced differentiation of THP-1 monocytic cells into macrophages. We found that MMP1, MMP8, MMP3, MMP10, MMP12, MMP19, MMP9, and MMP7 were upregulated during differentiation whereas MMP2 remained unchanged. Expression of MMPs increased in a time-dependent manner; MMP1, MMP8, MMP3, MMP10, and MMP12 increased beginning at 60 hr post PMA treatment whereas MMP19, MMP9, and MMP7 increased beginning at 24 hr post PMA treatment. To identify signal transduction pathways involved in PMA-induced upregulation of MMPs, we treated PMA-differentiated THP-1 cells with specific inhibitors for PKC, MEK1, NF-${\kappa}B$, PI3K, p38 MAPK and PLC. We found that inhibition of the MEK1 pathway blocked PMA-induced upregulation of all MMPs to varying degrees except for MMP-2. In addition, expression of select MMPs was inhibited by PI3K, p38 MAPK and PLC inhibitors. In conclusion, we show that of the MMPs examined, most MMPs were up-regulated during differentiation of monocyte into macrophage via the MEK1 pathway. These results provide basic information for studying MMPs expression during macrophage differentiation.