• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1519-1529
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• 2016

Background: Matrix metalloproteinase -2 (gelatinase-A, Mr 72,000 type IV collagenase, MMP-2) and -9 (gelatinase-B, Mr 92,000 type IV collagenase, MMP-9) are key molecules that play roles in tumor growth, invasion, tissue remodeling, metastasis and stem-cell regulation by digesting extracellular matrix barriers. MMP-2 and -9 are well known to impact on solid cancer susceptibility, whereas, in hematological malignancies, a paucity of data is available to resolve the function of these regulatory molecules in bone marrow mononuclear cells (BM-MNCs) and stromal cells of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Objectives: The present study aimed to investigate mRNA expression and gelatinase A and B secretion from BM-MNCs in vitro and genotypic associations of MMP-2 (-1306 C/T; rs243865), MMP-9 (-1562 C/T; rs3918242), tissue inhibitor of metalloproteinase -1 (TIMP-1) (372T/C; rs4898, Exon 5) and TIMP-2 (-418G/C; rs8179090) in MDS and AML. Results: The study covered cases of confirmed MDS (n=50), AML (n=32) and healthy controls (n=110). MMP-9 mRNA expression revealed 2 fold increased expression in MDS-RAEB II and 2.5 fold in AML M-4 (60-70% blasts). Secretion of gelatinase-B also revealed the MMP-9 mRNA expression and ELISA data also supported these data. We noted that those patients having more blast crises presented with more secretion of MMP-9 and its mRNA expression. In contrast MMP-9 (-1562 C/T) showed significant polymorphic associations in MDS (p<0.02) and AML (p<0.02). MMP-9 mRNA expression of C/T and T/T genotypes were 1.5 and 2.5 fold increased in MDS and AML respectively. In AML, MMP-2 C/T and T/T genotypes showed 2.0 fold mRNA expression. Only MMP-9 (-1306 C/T) showed significant 4 fold (p<0.001) increased risk with chemical and x-ray exposed MDS, while tobacco and cigarette smokers have 3 fold (p<0.04) risk in AML. Conclusions: In view of our results, MMP-9 revealed synergistic secretion and expression in blast crises of MDS and AML with 'gene' polymorphic effects and is significantly associated with increased risk with tobacco, cigarette and environmental exposure. Release and secretion of these enzymes may influence hematopoietic cell behavior and may be important in the clinical point of view. It may offer valuable tools for diagnosis and prognosis, as well as possible targets for the treatments.

• Animal cells and systems
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• v.10 no.2
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• pp.79-83
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• 2006

Tissue plasminogen activator (tPA) is used to lyse clots and reperfuse brain in ischemic stroke. However, sideeffects of intracerebral hemorrhage (ICH) and edema limit their clinical application. In part, these phenomena has been linked with elevations in matrix metalloproteinase-9 (MMP-9) in neurovascular unit. However little is known about their regulatory signaling pathways in brain cells. Here, I examine the role of MAP kinase pathways in tPA-induced MMP-9 regulation in rat cortical astrocytes. tPA $(1-10\;{\mu}g/ml)$ induced dose-dependent elevations in MMP-9 and MMP-2 in conditioned media. Although tPA increased phosphorylation in two MAP kinases (ERK, JNK), only inhibition of the JNK pathway by the JNK inhibitor SP600126 significantly reduced MMP-9 upregulation. Neither ERK inhibition with U0126 nor p38 inhibition with SB203580 had any significant effects. Taken together, these results suggest that c-jun N-terminal kinase (JNK) plays an essential role for tPA-induced MMP-9 upregulation.

• 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.

• Journal of Periodontal and Implant Science
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• v.36 no.2
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• pp.409-425
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• 2006

치주질환의 병원균은 세포벽의 항원에 의하여 조직내 존재하는 mononuclear phagocytes가 활성화되어 cytokine들이 생성됨 으로써 치주 결체조직의 파괴를 진행시킨다. 이런 관련된 cytokine들은 순차적으로 상주하는 치은세포 및 대식세포가 Matrix metalloproteinase 합성을 하도록 유도하여 조직파괴를 시작한다. 이들 Matrix metalloproteinase중 MMP-2, MMP-9 (Gelatinase A,B)는 type IV collagen 및 변성된 interstitial collagen을 파괴하며 치주환자의 치은 열구액, 치은조직, 타액 네에서 높게 보고 되어왔다. 당뇨병은 치주질환의 위험요소중 하나로 달뇨 환자에서는 치주질환의 유병율이 일반인에 비해 높고 치주질환의 중증도도 더 심하여 진행도 빠르다고 알려져 있다. 그 병리 기전 중 하나로는 당뇨 환자에서는 치은 열구액 내 중성구 유래의 Matrix metalloproteinase의 활성 증가 및$TNF-{\alpha}$ 의 활성 증가가 추정되고 있다. 본 실험에서는 제2형 당뇨병 환자와 비당뇨 환자들에서 만성 치주염 부위의 치은 및 건강한 치은에서 염증매개체 중 하나인 MMP-2, MMP-9 및 $TNF-{\alpha}$ 의 발현에 대해 상호 비교 분석함으로서 염증, 혈당이 미치는 영향을 밝히고 제 2형 당뇨병 환자에서 심한 치주조직 파괴의 기전을 연구하고자 하였다. 경북대학교병원 치주과 내원환자 중 제2형 당뇨병 환자와 비당뇨 환자들 및 치주질환이 없는 건강인 대조군을 대상으로 여러 가지 환자요소, 임상 치주상태를 기록하고, 전신적으로 건강한 환자의 건강한 부위(n=8,Group 1), 전신적으로 건강한 환자으 만성 치주염 부위(n=8, Group 2), 제2형 당뇨병 환자의 만성 치주염 부위 (n=8,Group 3)에서 각각 변연치은을 채득하고 액화질소에 급속 동결하였다. Western blotting을 이용하여 각 조직 내 MMP-2, MMP-9 및 $TNF-{\alpha}$ 의 발현을 관찰, densitometer를 이용하여 상대적 발현을 정량, 각 조직의${\beta}-actin$을 이용하여 표준화하여 실험군과 대조군들의 평균치를 비교하였다. 비당뇨 환자들의 만성 치주염 부위 및 제2형 당뇨병 환자의 만성 치주염 부위에서 모두 건강 대조군에 비해 MMP-2와 MMP-9 의 발현이 증가되었다. 또한 MMP-2와 MMP-9는 2형 당뇨 환자의 만성 치주염 부위가 비당뇨 환자의 만성 치주염 부위보다 증가된 발현양상을 보였으며, $TNF-{\alpha}$ 발현 비교시 각 군간 유의성 있는 변화는 없었으나 2형 당뇨환자군에서 MMP-2 및 MMP-9의 증가와 함께 다소 증가 양상을 보였다. 결론적으로 본 실험에서 MMP-2 및 MMP-9의 증가가 만성 치주염 및 2형 당뇨 환자에서의 만성치주염에서 비당뇨환자 보다 MMP-2, MMP-9의 증가양상을 보여 주었으며 $TNF-{\alpha}$ 가 2형 당뇨환자의 만성치주염 진행과정에 기여인자로써 역할을 하는 것으로 생각된다.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5055-5060
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• 2013

Objective: Twist, a basic helix-loop-helix transcription factor, plays a key role in the metastatic progression of human cancer. Matrix metalloproteinase (MMP)-9 is an endopeptidase that digests basement membrane type IV collagen, therefore being possibly related to tumor progression. It has been reported that Twist and matrix metalloproteinase-9 (MMP-9) are expressed in gastric cancers. However, the exact roles of Twist and MMP-9 in tumor metastasis and prognosis remain unclear. The aim of this study was to casts light on this question. Methods:Twist and MMP-9 expression in tissue sections of 37 gastric carcinomas was evaluated with immunohistochemistry. The staining results were compared with clinicopatholgic features and to patients' outcome. Results: Twist positive expression was significantly increased in gastric cancer cases with lymph node metastasis (P=0.023). But no correlations were found between MMP-9 overexpression and clinicopathologic features, such as recurrence, TNM stage, and lymph node metastasis. Overall survival (OS) was significantly correlated with recurrence, serosa invasion, TNM stages, distant metastasis, and MMP-9 (P=0.027, 0.021, 0.000, 0.024 and 0.036, respectively). Disease-free survival (DFS) was prominently related to recurrence location, serosa invasion and TNM stages (P=0.000, 0.038 and 0.003, respectively). In the Cox regression multivariate analysis, TNM stage, distant metastasis and MMP-9 were significantly associated with prognosis of gastric cancer (P=0.002, 0.019, and 0.032, respectively). Conclusions: This study showed Twist positive expression to be significantly correlated with lymph node metastasis in gastric cancer. MMP-9 overexpression is associated with OS, suggesting that MMP-9 is a prognostic indicator for survival in patients with gastric cancer.

• Journal of Life Science
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• v.32 no.1
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• pp.51-55
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• 2022

Matrix metalloproteinase (MMP) enzymes are responsible for the degradation and formation of the extracellular matrix (ECM), and overproduction of MMPs is observed in several diseases, such as cancer and asthma, that progress with metastatic characteristics. Natural products, especially phytochemicals, have been an important source of MMP inhibitors with reduced side effects. Although the majority of phytochemicals inhibit the enzymatic activity of MMPs, some suppress MMP production. In this context, the current study evaluated the potential of Corydalis heterocarpa, a halophyte with reported bioactivities, to inhibit MMP expression in PMA-stimulated HT-1080 cells. A crude C. heterocarpa extract was shown to decrease the mRNA and protein expression of MMP-2 and MMP-9 while increasing the endogenous MMP inhibitors TIMP-1 and TIMP-2 which regulate MMP expression in healthy tissues. In addition, our results show that the inhibitory effects of C. heterocarpa might occur through suppression of the phosphorylation of MAPK signaling, the upstream activator of MMP overexpression. In conclusion, C. heterocarpa is a potential source of antimetastatic compounds that might serve as lead molecules to develop novel MMP inhibitors.

• Journal of Embryo Transfer
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• v.33 no.3
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• pp.99-105
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• 2018

To determine the differences in the in-vitro ovum maturation process of bovine, we compared the expression of MMPs in these oocytes and cumulus cell throughout oocytes maturated. In an attempt to investigate the effect of MMP activation and inhibitors in total protein of cumulus cell and, oocytes during oocytes maturation, we examined and monitored the localization and expression of MMPs (MMP-2 and MMP-9), TIMPs (TIMP-2 and TIMP-3), as well as their expression profiles (Real-time PCR, Gelatin Zymography and ELISA). Our results that the bovine oocytes MMP-2 and MMP-9 level was significantly associated with the rate of maturity of oocytes (P<0.05). In cumulus cell, MMP-2 was highly expressed in all stages of the oocyte's maturation. The final oocytes maturation exhibited strong gelatinase activity. There was no significant correlation between cumulus cell MMP-9 and the maturation rate of oocytes. However, for the oocyte cytoplasm MMP-9 expression was significant correlation to the maturation oocytes. There was no significant correlation between cumulonimbus cells MMP-9 and oocyte maturation rates; however, for oocyte cytoplasm, MMP-9 expression was significantly correlated with mature oocyte. However, the TIMP-1 and TIMP-2 protein expression patterns are not correlated with the maturation rate of the oocyte. Our results suggest that MMP different expression pattern may regulate the morphological remodeling of oocyte's in the cumulus cell. Further, the MMP-2 expression has a strong relation with a higher maturation rate of the oocyte.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.3
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• pp.2113-2118
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• 2013

Aim and Background: Cervical cancer remains the third most common cancer in women globally after breast and colorectal cancer. Well-characterized biomarkers are necessary for early diagnosis and to predict metastatic progression and effective therapy. MiRNAs can regulate gene expression, cell growth, differentiation and apoptosis by targeting mRNAs for translational repression or degradation in tumor cells. The present study was conducted to assess expression of miR93, miR200a, RECK, MMP2, MMP9 in invasive cervical carcinoma, and analyze their clinical significance. Method: A total of 116 patients with invasive cervical carcinoma and 100 patients undergoing hysterectomy for benign lesions were retrospectively examined. Quantitative real-time PCR was performed to determine expression of miR93 and miR200a while RECK, MMP2, MMP9 and MVD were assessed by immunohistochemical staining. Results: Cervical carcinoma patients demonstrated up-regulation of miR-93, miR-200a, MMP2 and MMP9, with down-regulation of RECK as compared to benign lesion tissues. RECK was significantly inversely related to invasion and lymphatic metastasis. The 5-year survival rate for patients with strong RECK expression was significantly higher than that with weakly expressing tumors. Conclusion: MiR-93 and miR-200a are associated with metastasis and invasion of cervical carcinoma. Thus together with RECK they are potential prognostic markers for cervical carcinoma. RECK cooperating with MMP2, MMP9 expression is a significant prognostic factor correlated with long-term survival for patients with invasive cervical carcinoma.

• Journal of Physiology & Pathology in Korean Medicine
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• v.18 no.6
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• pp.1694-1698
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• 2004

We hope to evaluate the effects of Sabaek-san for the bronchial asthma using assesment on the metrix metalloproteinase-9(MMP-9) after Sabaek-san was intravenously administered OVA-sensitized and -challenged mice. Seventy-two female mice, 8-10 weeks of age and free of murine specific pathogens, were used. Of the seventy-two mice, twenty-four mice were not sensitized and forty-eight mice were sensitized by intraperitoneal injection of OVA. Of the sensitized mice, twenty-four mice didn't administrate Sabaek-san and twenty-four administrated Sabaek-san. Mice were sensitized on days 1 and 14 by intraperitoneal injection of 20 fig OVA. On days 21, 22 and 23 after the initial sensitization, the mice were challenged for 30 minutes with an aerosol of 1% OVA in saline. Sabaek-san administered 200㎎/㎏ in the tail of the mouse, one time per day, for 7 days, beginning 14 days after first sensitization. Bronchoalveolar lavage was performed 72 hours after the last challenge, and total cell numbers in the BAL fluid were count. Also, level of MMP-9 in the BAL fluid were measured by Enzyme immunoassays and Western blot analysis. Enzyme immunoassay revealed that MMP-9 levels in the BAL fluids significantly increased 72 h after OVA inhalation compared with levels in the control group. After administration of the Sabaek-san, the levels of the MMP-9 in BAL fluids 72 h after OVA inhalation reduced dramatically. Western blot analysis revealed that MMP-9 levels increased in the all mice which were challenge with OVA without administered Sabaek-san compared the normal mouse. However, in the groups of the administered Sabaek-san, the MMP-9 level markedly decreased. Sabaek-san might be effect the treatment of the bronchial asthma as a inhibition of the MMP-9.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.6
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• pp.3681-3684
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• 2013

Deregulated miRNAs participate in osteosarcoma genesis. In this study, the expression of miRNA-218 in human osteosarcomas, adjacent normal tissues and Saos-2 human osteosarcoma cells was first assessed. Then the precise role of miRNA-218 in osteosarcoma cells was investigated. Upon transfection with a miR-218 expression vector, the proliferation of Saos-2 human osteosarcoma cells determined using the ATPlite assay was significantly suppressed, whilw migration of Saos-2 cells detected by wound healing and invasion determined using transwells were dramatically inhibited. Potential target genes of miR-218 were predicted and T-cell lymphoma invasion and metastasis 1 (TIAM1) and matrix metalloproteinase 2 (MMP2) and 9 (MMP9) were identified. This was confirmed by western blotting, which showed that miR-218 expression inhibited TIAM1, MMP2 and MMP9 protein expression. Collectively, these data suggest that miR-218 acts as a tumor suppressor in osteosarcomas by down-regulating TIAM1, MMP2 and MMP9 expression.