• The korean journal of orthodontics
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• v.28 no.1 s.66
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• pp.165-174
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• 1998

The turnover of collagen is controlled by the balance between collagen synthesis and degradation. The production of collagenase (matrix metalloproteinase-1) and its inhibitor, tissue inhibitor of matrix metallopmteinase-1 (TIMP-1) are one of the substances which regulate this balance. The periodontal ligament fibroblast plays an important role in collagen metabolism during orthodontic treatment and is believed to be an origin of the osteoblast in the alveolar bone. The collagenase secreted by the periodontal ligament fibroblast and the osteoblast initiates the bone resorption by removing the osteoid layer in the alveloar bone. The interleukin-$1{\beta}$ is secreted by the macrophage during orthodontic treatment. The present study was undertaken to assess the effect of mechanical stress and interleukin-$1{\beta}$ on the expression of collagenase and TIMP-1 in the periodontal ligament fibroblasts using reverse transcription polymerase chain reaction and immunohistochemical staining. The periodontal ligament fibroblasts were stitched by placing the $Petriperm dish^{\circledR}$ dish on the top of spheroidal convex watch glass ($5\%$ surface increase) and tented with interleukin-$1{\beta}$ (1.0 ng/ml), or treated with both of them. Treatment with mechanical stress and/or interleukin-$1{\beta}$ resulted in increased collagenase mRNA expression. The mechanical stress treated group (1.61, 1.62, 1.37 fold increase), the interleukin-$1{\beta}$, tented group (1.68, 1.60, 3.78 fold increase), the mechanical stress and interleukin-$1{\beta}$ treated group (1.89, 1.72, 5.48 fold increase) induced increases in collagenase mRNA compared with the control group after 2, 4, 8 hours respectively. But TIMP-1 mRNA expressions at experimental groups were decreased after 2, 4 hours and increased after 8 hours. The mechanical stress treated group (0.16, 0.49 fold decrease and 3.77 fold increase), the interleukin-$1{\beta}$ treated group (0.15,0.44 fold decrease and 4.46 fold increase), the mechanical stress and interleukin-$1{\beta}$ tented group (0.15, 0.69 fold decrease and 4.81 fold increase) induced changes in TIMP-1 mRNA compared with the control group after 2, 4, 8 hours, respectively. Immunohistochemical stain showed that increased collagenase and TIMP-1 staining of the mechanical stress tented group, the interleukin-$1{\beta}$ treated group, and the mechanical stress and interleukin-$1{\beta}$ treated group compared with that of the control group after 8 hours. These findings suggest that mechanical stress and interleukin-$1{\beta}$ regulate expression of collagenase and TIMP-1.

• Biomolecules & Therapeutics
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• v.25 no.2
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• pp.213-221
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• 2017

Baicalein, a natural flavonoid obtained from the rhizome of Scutellaria baicalensis Georgi, has been reported to have anticancer activities in several human cancer cell lines. However, its antimetastatic effects and associated mechanisms in melanoma cells have not been extensively studied. The current study examined the effects of baicalein on cell motility and anti-invasive activity using mouse melanoma B16F10 cells. Within the noncytotoxic concentration range, baicalein significantly inhibited the cell motility and invasiveness of B16F10 cells in a concentration-dependent manner. Baicalein also reduced the activity and expression of matrix metalloproteinase (MMP)-2 and -9; however, the levels of tissue inhibitor of metalloproteinase-1 and -2 were concomitantly increased. The inhibitory effects of baicalein on cell motility and invasiveness were found to be associated with its tightening of tight junction (TJ), which was demonstrated by an increase in transepithelial electrical resistance and downregulation of the claudin family of proteins. Additionally, treatment with baicalein markedly reduced the expression levels of lipopolysaccharide-induced phosphorylated Akt and the invasive activity in B16F10 cells. Taken together, these results suggest that baicalein inhibits B16F10 melanoma cell migration and invasion by reducing the expression of MMPs and tightening TJ through the suppression of claudin expression, possibly in association with a suppression of the phosphoinositide 3-kinase/Akt signaling pathway.

• Journal of Applied Biological Chemistry
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• v.61 no.4
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• pp.417-421
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• 2018

Ultraviolet rays are electromagnetic waves with a shorter wavelength than visible light, and ultraviolet rays that pass through the ozone layer are the main cause of skin aging. Chronic exposure of skin tissue to ultraviolet light activates the Mitogen-activated Protein Kinases (MAPKs) signaling pathways in human keratinocytes, resulting in increased production of matrix metalloproteinases (MMPs). In this study, we investigated the herbal extracts from Jeju Island on the anti-aging effect in human keratinocytes (HaCaTs) by ultraviolet stimulation. We examined that herb extract from Jeju Island were decreased in anti-aging activity on measuring the level of MMP-1 gene and protein expression in ultraviolet-induced keratinocytes. As a result, it was confirmed that Thymus quinquecostatus extract (TQE) significantly reduced the expression of MMP-1 in a dose-dependent manner by UV irradiated HaCaTs. According to our data, TQE significantly attenuated UV-induced phosphorylation of the MAPKs signaling elements ERK1/2, JNK1/2 and p38 proteins. These results suggest that the MAPKs pathway may contribute to the inhibitory effect of TQE on UV-induced MMP-1 production in human keratinocytes. Our results suggest that TQE may be a protective agent against skin aging by preventing UV-induced MMP-1 production.

• International Journal of Oncology
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• v.54 no.2
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• pp.753-763
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• 2019

The mutation of isocitrate dehydrogenase (IDH)1 (R132H) and IDH2 (R172K) and the induction of hypoxia in various solid tumors results in alterations in metabolic profiles, including the production of the d- or l-forms of 2-hydroxyglutarate (2HG) from α-ketoglutarate in aerobic metabolism in the tricarboxylic acid (TCA) cycle. However, it is unclear whether the oncometabolite d-2HG increases angiogenesis in endothelial cells. Therefore, in this study, we analyzed the levels of various metabolites, including d-2HG, under hypoxic conditions and in IDH2R172K mutant breast cancer cells by mass spectrometry. We then further evaluated the effects of this metabolite on angiogenesis in breast cancer cells. The results revealed that treatment with d-2HG increased the levels of secreted vascular endothelial growth factor (VEGF) in cancer cells and enhanced endothelial cell proliferation in a concentration-dependent manner. Wound healing and cell migration (examined by Transwell assay) were significantly increased by d-2HG to a level similar to that induced by VEGF. Tube formation was significantly stimulated by d-2HG, and chick chorioallantoic membrane angiogenesis was also enhanced by d-2HG. d-2HG activated VEGF receptor (VEGFR)2 and VEGFR2 downstream signaling, extracellular signal-regulated kinase 1/2, focal adhesion kinase, AKT and matrix metalloproteinase (MMP)2. Taken together, the findings of this study suggested that d-2HG induced angiogenic activity via VEGFR2 signaling and increased MMP2 activity.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.12
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• pp.4989-4994
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• 2014

Background: It has been reported that COX-2 expression is associated with MMP-2 expression in thyroid and breast cancers, suggesting that MMPs are linked to COX-2-mediated carcinogenesis. Several polymorphisms within the MMP2 promoter region have been reported in cases with oncogenesis and tumor progression, especially in colorectal carcinogenesis. Materials and Methods: This research evaluated risk of association of the SNPs, including genes for COX-2 (AIG transition at +202) and MMP-2 (Crr transition at-1306), with colorectal cancer in 125 patients and 125 healthy controls. Results and Conclusions: Our data confirmed that MMP2 C-1306 T mutations were significantly more common in colon cancer patients than in our control Saudi population; p=O.0121. On the other hand in our study, there was no significant association between genotype distribution ofthe COX2 polymorphism and colorectal cancer; p=0.847. An elevated frequency ofthe mutated genotype in the control group as compared to the patients subjects indeed suggested that this polymorphism could decrease risk in the Saudi population. Our study confirmed that the polymorphisms that could affect the expressions of MMP-2 and COX-2 the colon cancer patients were significantly higher than that in the COX-2 negative group. The frequency of individuals with MMP2 polymorphisms in colon cancer patients was higher than individuals with combination of COX2 and MMP2 polymorphisms. Our study confirmed that individuals who carried the polymorphisms that could affect the expressions ofCOX2 are more susceptible to colon cancer. MMP2 regulatory polymorphisms could be considered as protective; further studies need to confirm the results with more samples and healthy subjects.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.6
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• pp.2853-2856
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• 2012

Background: Previous studies assessing associations between matrix metalloproteinase 2 (MMP-2) polymorphisms and lung cancer risk reported conflicting results. A meta-analysis was therefore performed to derive a more precise estimation. Method: Case-control studies assessing associations between MMP-2 C735T and C1306T polymorphisms and lung cancer risk were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. Results: 7 studies with a total of 3,189 lung cancer cases and 3,013 controls were finally included into this meta-analysis. Overall, the MMP-2 C735T polymorphism was associated with lung cancer risk under the homozygote model (CC versus TT: OR =1.44, 95% CI = 1.03-2.02, $I^2$ = 0%), while the MMP-2 C1306T polymorphism also associated demonstrated links with all four models (all P values less than 0.05). Subgroup analyses by race suggested obvious associations between MMP-2 C735T and C1306T polymorphisms and lung cancer risk in Asians but not in Caucasians. There was no evidence for publication bias. Conclusion: Currently available evidence supports teh conclusion that MMP-2 C735T and C1306T polymorphisms influence susceptibility to lung cancer in Asians.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5577-5582
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• 2014

Objective: To observe the effects of metastasis-associated tumor gene family 2 (MTA2) depletion on human breast cancer cell proliferation and metastasis. Methods: A short-hairpin RNA targeting MTA2 was chemically synthesized and transfected into a lentivirus to construct Lv-shMTA2 for infection into the MDA-MB231 human breast cancer cell line. At 48 hours after infection cells were harvested and mRNA and protein levels of MTA2 were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. Cell viability and metastasis were assessed by CCK-8, wound-healing assay and Transwell assay, respectively. In addition, a xenograft model of human breast cancer was constructed to investigate cancerous cell growth and capacity for metastasis. Results: After infection with Lv-shMTA2, mRNA and protein levels of MTA2 was significantly reduced (p<0.05) and MDA-MB231 cell proliferation and metastasis were inhibited (p<0.05). In addition, mean tumor size was smaller than that in control group nude mice (p<0.05) and numbers of metastatic deposits in lung were lower than in control group mice (p<0.05). Depletion of MTA2 affected MMP-2 and apoptosis-related protein expression. Conclusions: For the first time to our knowledge we showed that MTA2 depletion could significantly inhibit human breast cancer cell growth and metastasis, implying that MTA2 might be involved in the progression of breast cancer. The role of MTA2 in breast cancer growth and metastasis might be linked with regulation of matrix metalloproteinase and apoptosis.

• 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.

• Biomolecules & Therapeutics
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• v.31 no.2
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• pp.210-218
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• 2023

Prostate cancer is the fifth leading cause of cancer-related mortality in men, primarily because of treatment resistance, recurrence, and metastasis. In the present study, we investigated the role of paracrine interleukin-8 (IL-8) in the antagonistic expression of IL-8 and androgen receptor (AR), and the contribution of IL-8 to prostate cancer aggressiveness. In hormone-responsive LNCaP cells that do not express IL-8, recombinant IL-8 treatment significantly increased expressions of IL-8, CXC chemokine receptor 2 (CXCR2), matrix metalloproteinase (MMP)-2/9, Snail, and vimentin. IL-8 treatment significantly decreased AR and E-cadherin expression. IL-8-induced gene expression changes were suppressed by navarixin, a CXCR1/2 inhibitor, and gallein, a Gβγ inhibitor. In PC-3 androgen-refractory prostate cancer cells, IL-8 knockdown reduced expressions of CXCR2, MMP-2/9, Snail, and vimentin, and increased AR and E-cadherin expressions at the mRNA and protein levels. Co-culture with MEG-01 human megakaryocytic cells secreting high levels of IL-8 induced gene expression changes in both LNCaP and PC-3 cells, similar to those induced by IL-8 treatment. The altered gene expressions were accompanied by significant activation of transcription factor Snail in LNCaP and PC-3 cells. Treatment with the CXCR blocker navarixin inhibited the invasion of PC-3 cells but not LNCaP cells. However, invasion induced by MEG-01 was inhibited by navarixin in both LNCaP and PC-3 cells. The collective findings demonstrate that IL-8 enhances CXCR2 expression, which antagonistically regulates AR expression. More importantly, through changes in IL-8/CXCR2-regulated gene expression, IL-8 induces antiandrogen therapy resistance and epithelial-mesenchymal transition in prostate cancer.

• Radiation Oncology Journal
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• v.19 no.2
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• pp.181-189
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• 2001

Purpose : Changes in the balance between MMP and TIMP can have a profound effect on the composition in the extracellular matrix (ECM) and affect various cellular functions including adhesion, migration, differentiation of cells, and fibrosis and invasion and metastasis of cancer cells. Radiation therapy is a popular treatment modality for benign and malignant tumor, but the study for radiation effect on MMP and TIMP is scarce. In the current study, we have examined the expression of TIMP in fibrosis-prone (C57BL/6) mice after radiation. Methods and Materials : Adult female mice of $10\~12$ weeks were used. The whole body were irradiated using a Varian CL-4/100 with 2 and 10 Gy. Immunohistochemical staining was peformed according to Avidin Biotin complex method and evaluated by observing high power field. For TIMP-1, TIMP-2 antibodies, reactivity was assessed in the parenchymal cell and in the stromal cell. The scale of staining was assessed by combining the quantitative and qualiative intensity of staining. Results : TIMP-1 immunoreactivity did not change in lung. But, in liver, TIMP-1 immunoreactivity was localized in cytoplasm of hepatocyte and Kupffer cell. in kidney, TIMP-1 immunoreactivity was localized in cytoplasm of some tubular cell. Temporal variations were not seen. Dose-response relationship was not seen except kidney. TIMP-2 immunoreactivity in lung was a score (++) at 0 Gy and elevated to a score (+++) at 2 Gy. TIMP-2 immunoreactivity was a score (++) in liver at 0 Gy. TIMP-2 immunoreactivity was localized in cytoplasm of hepatocyte and Kupffer cell as same as patterns of TIMP-1 immunoreactivity. The TIMP-2 immunoreactivity in liver was elevated to (+++) at 2 Gy. Immunoreactivity to TIMP-2 in kidney was a score (+++) at 0 Gy and was not changed at 10 Gy. The score of TIMP-2 immunoreactivity was reduced to (++) at 2 Gy. TIMP-2 immunoreactivity was confined to tubules in kidney. Temporal variation of TIMP-2 immunoreactivity was irregular. Dose-response relationship of TIMP-2 immunoreactivity was not seen. Conclusions : Differences between intensity of expression of TIMP-1 and TIMP-2 in each organ was present. Expression of TIMP was localized to specific cell in each organ. Irradiation increased TIMP-1 immunoreactivity in the liver and the kidney. Irradiation increased TIMP-2 immunoreactivity in the lung. But, in the liver and the kidney, TIMP-2 expression to radiation was irregular. Temporal variation of TIMP-2 immunoreactivity was irregular. Dose-response relationship of TIHP-2 immunoreactivity was not seen. In the future, we expect that the study of immunohistochemical staining of longer period of postirradiation and quantitative analysis using western blotting and northern blotting could define the role of TIMP in the radiation induced tissue fibrosis.