• Asian Pacific Journal of Cancer Prevention
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• 제13권6호
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• pp.2903-2908
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• 2012

Background: Matrix metalloproteinase-9 (MMP-9) is associated with disruption of basement membranes of blood vessels and promotion of metastasis through the lymphatics. However, its prognostic value for survival in patients with gastric cancer remains controversial. Method: We therefore conducted a meta-analysis of the published literature in order to clarify the impact of MMP-9. Clinical studies were selected for further analysis if they provided an independent assessment of MMP-9 in gastric cancer and reported analysis of survival data according to MMP-9 expression. Results: A total of 11 studies, covering 1700 patients, were included for meta-analysis. A summary hazard ratio (HR) of all studies and sub-group hazard ratios were calculated. The combined HR suggested that a positive MMP-9 expression had an impact on overall survival: 1.25 (95% confidence interval 1.11-1.40) in all eligible studies; 1.13 (1.06-1.20) in 8 studies detecting MMP-9 by immunohistochemistry; 1.36 (1.12-1.65) in 7 studies from Asia. Only one study for DFS showed a significant impact on disease free survival (HR 1.73, 95%CI 1.27-2.34). Conclusions: Our findings suggested that MMP-9 protein expression might be a factor for a poor prognosis in patients with gastric cancer. However, the association was rather weak, so that more prospective studies should further explore the prognostic impact of MMP-9 mRNA and correlations between MMP-9 and clinicopathological characteristics.

• Asian Pacific Journal of Cancer Prevention
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• 제13권3호
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• pp.1049-1052
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• 2012

The purpose of this study was to evaluate expression and prognostic value of matrix metalloproteinase-7 (MMP-7) in colorectal cancer (CRC) patients. CRC tissues and corresponding distal normal mucosa tissues of 118 CRC patients were assessed by immunohistochemistry. Correlations between MMP-7 expression, patients' clinic pathological features, and overall survival rate were analyzed. We found that positive expression of MMP-7 in CRC tissues was significantly higher than that in distal normal mucosa (61.0% vs. 39.8%, p =0.001). Poor histological differentiation, advanced clinical stage and lymph node metastasis were significantly correlated with MMP-7 expression in CRC. The overall survival rate was significantly higher in the MMP-7 negative group than the positive group (Log-rank test= 9.957, p= 0.002). MMP-7 appeared as a significant independent prognostic factor through multivariate survival analysis. Collectively, we found MMP-7 expression to be correlated with progression and metastasis of CRC and thus could be used as a predictive marker of prognosis in CRC patients.

• Molecules and Cells
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• 제38권2호
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• pp.151-155
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• 2015

Matrix metalloproteinase (MMP)-9 degrades type IV collagen in the basement membrane and plays crucial roles in several pathological implications, including tumorigenesis and inflammation. In this study, we analyzed the effect of flavonols on MMP-9 expression in phorbol-12-myristate-13-acetate (PMA)-induced human fibrosarcoma HT-1080 cells. Galangin and kaempferol efficiently decreased MMP-9 secretion, whereas fisetin only weakly decreased its secretion. Galangin and kaempferol did not affect cell viability at concentrations up to $30{\mu}M$. Luciferase reporter assays showed that galangin and kaempferol decrease transcription of MMP-9 mRNA. Moreover, galangin and kaempferol strongly reduce $I{\kappa}B{\alpha}$ phosphorylation and significantly decrease JNK phosphorylation. These results indicate that galangin and kaempferol suppress PMA-induced MMP-9 expression by blocking activation of NF-${\kappa}B$ and AP-1. Therefore, these flavonols could be used as chemopreventive agents to lower the risk of diseases involving MMP-9.

• 생명과학회지
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• 제31권12호
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• pp.1100-1109
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• 2021

염생식물인 비쑥은 식용이 가능한 약용식물로서 살충, 항염, 항콜레스테롤, 해열, 항균 활성 등이 알려져 있다. 본 연구에서는 phorbol-12-myristate-13-acetate (PMA)로 자극된 인간 섬유육종 HT-1080 세포에서 5가지 활성검색방법 즉 : gelatin zymography, MMPs ELISA, wound healing assay, reverse transcription-polymerase chain reaction (RT-PCR), Western blot을 이용하여 비쑥의 조추출물과 그 용매 분획물의 MMP-2와 MMP-9 효소 활성에 대한 저해 효과를 평가하였다. 비쑥 시료들을 메틸렌 클로라이드(MC)와 메탄올(MeOH)로 각각 2번 추출하여 합한 것을 조추출물로 사용하였으며 이 조추출물은 MMP-2와 MMP-9 효소활성에 대해 유의한 억제 효과를 나타내었다. 이 조추출물은 용매극성에 따라 다시 n-hexane, 85% aq.MeOH, n-butanol 및 물 분획층으로 분획되었으며 이렇게 얻어진 4개의 용매 분획물들중에 n-hexane과 85% aq.MeOH 분획이 gelatin zymography와 MMP ELISA assay에서 MMP-2와 MMP-9의 활성을 효과적으로 억제하였다. 또한 wound healing assay, RT-PCR 및 Western blot assay에서 H₂O 분획을 제외한 모든 용매 분획물들이 세포 이동, 그리고 MMP-2 및 MMP-9의 mRNA와 단백질 발현을 유의하게 억제하였다.

• 분석과학
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• 제28권6호
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• pp.361-369
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• 2015

골관절염에 대한 참당귀 추출분말 (AGE)의 치료효과를 검토하고자 토끼연골세포와 흰쥐의 monosodium iodoacetate (MIA)로 유발된 골관절염 부위에서 시료를 채취하여 MMPs의 발현에 대한 AGE의 억제 효능을 검토하였다. 고 농도의 AGE (50 μg/mL) 투여에서 세포독성은 관찰되지 않았으며 면역 및 염증반응과 관련된 여러 인자의 전사인자인 NF-κB 활성화를 효과적으로 억제시켰다. 토끼연골 세포에서 MMP-2와 MMP-9의 활성을 확인해본 결과 AGE는 MMP-9의 활성을 효과적으로 억제시키는 것을 확인하였다. AGE를 토끼연골세포에 처리하여 분석한 결과, 주요성분인 decursin과 decursinol angelate가 3.62±0.47 μg/mg protein와 2.14±0.36 μg/mg protein으로 검출되었다. 동물실험을 위하여, 골관절염은 MIA를 흰쥐 무릎관절에 처리하여 동물모델을 만들었으며, 매일 25, 50와 100 mg/kg의 AGE를 3주 동안 먹인 결과 흰쥐의 연골 조직에서 MMPs가 억제되는 것을 확인하였다. 연골조직으로부터 RT-PCR을 통해 collagen Type I, collagen Type II, aggrecan 및 MMPs (MMP-3, MMP-9, MMP-13)의 mRNA를 확인해본 결과 AGE는 collagen Type I, collagen Type II, aggrecan은 증가시키며 MMPs는 감소시키는 효과를 얻었다. 결론적으로 AGE는 MMPs 억제를 통하여 골관절염의 발생을 억제한다.

• Molecules and Cells
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• 제39권2호
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• pp.103-110
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• 2016

As a degenerative joint disease, osteoarthritis (OA) constitutes a major cause of disability that seriously affects the quality of life of a large population of people worldwide. However, effective treatment that can successfully reverse OA progression is lacking until now. The present study aimed to determine whether two small non-coding RNAs miR-29a and miR-140, which are significantly down-regulated in OA, can be applied together as potential therapeutic targets for OA treatment. MiRNA synergy score was used to screen the miRNA pairs that potentially synergistically regulate OA. An in vitro model of OA was established by treating murine chondrocytes with IL-$1{\beta}$. Transfection of miR-29a and miR-140 via plasmids was investigated on chondrocyte proliferation and expression of nine genes such as ADAMTS4, ADAMTS5, ACAN, COL2A1, COL10A1, MMP1, MMP3, MMP13 and TIMP metallopeptidase inhibitor 1 (TIMP1). Western blotting was used to determine the protein expression level of MMP13 and TIMP1, and ELISA was used to detect the content of type II collagen. Combined use of miR-29a and miR-140 successfully reversed the destructive effect of IL-$1{\beta}$ on chondrocyte proliferation, and notably affected the MMP13 and TIMP1 gene expression that regulates extracellular matrix. Although co-transfection of miR-29a and miR-140 did not show a synergistic effect on MMP13 protein expression and type II collagen release, but both of them can significantly suppress the protein abundance of MMP13 and restore the type II collagen release in IL-$1{\beta}$ treated chondrocytes. Compared with single miRNA transfection, cotransfection of both miRNAs exceedingly abrogated the suppressed the protein production of TIMP1 caused by IL-$1{\beta}$, thereby suggesting potent synergistic action. These results provided1novel insights into the important function of miRNAs' collaboration in OA pathological development. The reduced MMP13, and enhanced TIMP1 protein production and type II collagen release also implies that miR-29a and miR-140 combination treatment may be a possible treatment for OA.

• Asian Pacific Journal of Cancer Prevention
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• 제13권11호
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• pp.5709-5714
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• 2012

Objective: To evaluate the effects of curcumin on matrixmetalloproteinase-9 (MMP-9) and invasion ability induced by transforming growth factor-${\beta}1$ (TGF-${\beta}1$) in MDA-MB-231 cells and potential mechanisms. Methods: Human breast cancer MDA-MB-231 cells were used with the CCK-8 assay to measure the cytotoxicity of curcumin. After treatment with 10 ng/ml TGF-${\beta}1$, with or without curcumin (${\leq}10{\mu}M$), cell invasion was checked by transwell chamber. The effects of curcumin on TGF-${\beta}1$-stimulated MMP-9 and phosphorylation of Smad2, extracellular-regulated kinase (ERK), and p38 mitogen activated protein kinases (p38MAPK) were examined by Western blotting. Supernatant liquid were collected to analyze the activity of MMP-9 via zymography. Following treatment with PD98059, a specific inhibitor of ERK, and SB203580, a specific inhibitor of p38MAPK, Western blotting and zymography were employed to examine MMP-9 expression and activity, respectively. Results: Low dose curcumin (${\leq}10{\mu}M$) did not show any obvious toxicity to the cells, while $0{\sim}10{\mu}mol/L$ caused a concentration-dependent reduction in cell invasion provoked by TGF-${\beta}1$. Curcumin also markedly inhibited TGF-${\beta}1$-regulated MMP-9 and activation of Smad2, ERK1/2 and p38 in a dose- and time-dependent manner. Additionally, PD98059, but not SB203580, showed a similar pattern of inhibition of MMP-9 expression. Conclusion: Curcumin inhibited TGF-${\beta}1$-stimulated MMP-9 and the invasive phenotype in MDA-MB-231 cells, possibly associated with TGF-${\beta}$/Smad and TGF-${\beta}$/ERK signaling.

• Journal of Microbiology and Biotechnology
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• 제25권12호
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• pp.1997-2006
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• 2015

Ginsenoside Rg3 is a bioactive ginseng constituent that has been reported to have diverse pathological and physiological effects, including anti-inflammatory and anti-metastatic activities. Metastasis is one of the most important factors involved in patients with melanoma. However, the molecular mechanism underlying the anti-metastatic activities of Rg3 in malignant melanoma cancer has not been fully elucidated. In this study, we have evaluated that Rg3 effectively inhibits metastasis of B16F10 melanoma cancer cells. We found that Rg3 significantly suppresses the migration, invasion, wound healing, and colony-forming abilities of B16F10 cells in a dose-dependent manner. Mechanistically, we demonstrate that Rg3 suppresses B16F10 cell metastasis by inhibiting MMP-13 expression. These results indicate that Rg3 suppresses the metastasis of B16F10 mouse melanoma cancer cells via MMP-13 regulation. Importantly, MMP-13 downregulation may influence the migration and invasion capabilities of melanoma cells and has been correlated with melanoma progression. Therefore, Rg3 is a potential therapeutic candidate that could be used to treat patients with metastatic melanoma.

• Clinical and Experimental Pediatrics
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• 제57권12호
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• pp.526-532
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• 2014

Purpose: Matrix metalloproteinases (MMPs) have been implicated in atherosclerosis, and therefore, are considered risk factors for metabolic dysfunction in adults. However, there is little data on circulating levels of MMPs and tissue inhibitors of MMPs (TIMPs) with regard to obesity-related biomarkers in the general adolescent population. In the present study, we determined the associations of MMP-8, MMP-9, and TIMP-1 levels and MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios with obesity-related biomarkers in apparently healthy adolescent boys. Methods: We measured MMP and TIMP concentrations in plasma samples using the enzyme-linked immunosorbent assay and analyzed their associations with obesity-related biomarkers, such as liver enzymes and lipid profiles, in a sample of 91 Korean boys aged 13-14 years who participated in a general health check-up. Results: The mean age of the boys was $13.8{\pm}0.3years$; 72 boys were normal weight and 19 were overweight/obese. The Pearson correlation coefficients revealed a significant correlation between MMP-8 and aspartate aminotransferase (r=0.217, P=0.039) and alanine aminotransferase (r=0.250, P=0.017) and between TIMP-1 and aspartate aminotransferase (r=0.267, P=0.011). In a multivariate linear regression analysis, serum alanine aminotransferase was positively associated with the MMP-8 level. There were no significant differences in the MMP-8, MMP-9, and TIMP-1 levels or MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios between control and overweight/obese subjects. Conclusion: We found a significant association between the MMP-8 level and alanine aminotransferase in the apparently healthy adolescent boys. These findings indicate that there may be a pathophysiological mechanism underlying the relationship between MMP-8 and liver enzymes in young adolescents.

• 분석과학
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• 제24권2호
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• pp.135-141
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• 2011

세포외 기질의 주요 단백질 구성요소들을 가수분해시켜 재편성(turnover)과 재형성(remodeling)에 핵심 역할을 하는 효소가 matrix metalloproteinases (MMPs)이다. MMPs 중에서 MMP-2와 MMP-9는 catalytic domain이 fibronectin-like domain에 의해 hemopexin-like domain 부위와 떨어져 있는 점이 다른 MMP들과 다르다. MMP-9 억제제의 개발로 간암전이를 막을 수 있다고 보고되고 있다. Hovenia dulcis Thunberg에서 MMP-9의 활성을 저해하는 물질을 분리 정제하였고, 분리된 물질에 대한 MMP-9의 활성억제 여부를 확인하였다. Ethyl acetate (EA)에 의해 용출 분리된 두개의 화합물(화합물 A, 화합물 B)과 MeOH로 용출 분리된 한 개의 화합물(화합물 C)에서 MMP-9의 활성에 저해를 보였고, $^1H$와 $^{13}C$ NMR, GC-MS 그리고 IR로 이들의 구조를 분석하였다. 화합물 A는 hydroxyl기와 methoxyl기로 치환된 벤젠고리를 함유하는 화합물로 catechine 계열로 추정되었으며, 화합물 B와 C는 hydroxyl기와 methoxyl기로 치환된 벤젠 고리와 분자내 carbonyl기를 갖고 있는 nobiletin 계열의 화합물로 추정되었다. 그리고 화합물 A는 MMP-9 활성을 1.0%농도에서 76% 억제하였으며, 화합물 B는 동일한 농도에서 66% 억제하는 것으로 나타났다. 그리고 화합물 C는 1.0%농도에서 71% 억제하는 것으로 나타나 화합물 A가 MMP-9의 활성 저해능이 가장 좋은 것으로 나타났다.