• MMP-2
• MMP-9
• genotype
• phenotype
• polymorphism
• upper tract urothelial cancer

• cancer risk
• esophageal cancer
• matrix metalloproteinases
• polymorphisms

• Esophageal Neoplasms/genetics
• Genetic Predisposition to Disease/epidemiology
• Genetic Predisposition to Disease/genetics
• Humans
• Matrix Metalloproteinases/analysis
• Matrix Metalloproteinases/genetics
• Odds Ratio
• Polymorphism, Genetic/genetics
• Risk Factors

• SCC
• esophageal
• risk factor
• squamous cell carcinoma

• Ischemia
• MMP2
• MMP2-1306C/T
• Matrix metalloproteinases
• Polymorphism
• Retinal vein occlusion

• Aged
• Female
• Genetic Predisposition to Disease/genetics
• Humans
• Male
• Matrix Metalloproteinase 2/genetics
• Polymorphism, Genetic/genetics
• Retinal Vein Occlusion/genetics

• AGTR1
• Adiponectin
• GpIa/IIa
• MMP2
• RVO
• VKORC1

• Aged
• Eye Proteins/genetics
• Eye Proteins/metabolism
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• Genotype
• Greece/epidemiology
• Humans
• Male
• Ophthalmoscopy
• Polymorphism, Single Nucleotide
• Prevalence
• Retinal Vein Occlusion/diagnosis
• Retinal Vein Occlusion/epidemiology
• Retinal Vein Occlusion/genetics
• Retinal Vessels/diagnostic imaging
• Risk Factors

• Interleukin-8
• Matrix metalloproteinase-1
• Matrix metalloproteinase-13
• Oral squamous cell carcinoma
• Single nucleotide polymorphism

Background: Matrix metalloproteinases (MMPs) are capable of degrading and modifying most components of the extracellular matrix (ECM) and the basal membrane (BM), and play crucial roles in cancer invasion and metastasis. MMP gene expressions were regulated primarily at the transcriptional level, which was associated with tumor spread and patient prognosis. Polymorphisms in MMPs have been reported to be associated with non-small cell lung cancer (NSCLC). The objective of this study aim to evaluate the serum levels and polymorphisms of MMP-9 and MMP-13 in non-small cell lung cancer patients compared to normal subjects and their correlation to non-small cell lung cancer histopathology findings in Southern Chinese people. Methods: This case–control study included 245 patients with NSCLC and 258 healthy controls. Genomic DNA was extracted by using DNA extraction kit, genotyping was confirmed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct DNA sequencing, and serum levels of MMP-9 and MMP-13 were measured by using a specific ELISA, Human Matrix Metalloproteinase Enzyme Immunoassay Kits. Statistical analysis was carried out using the SPSS 23.0 software package. Results: The subjects carrying the TT genotype had a decreased risk of lung cancer in MMP9-1562C/T comparing with the CC genotype (p = 0.00, OR = 0.45, 95% CI = 0.29–0.68), and the MMP13-77 AA genotype was associated with a decreased risk of NSCLC by comparing with the GG genotype (p = 0.03, OR = 0.56, 95% CI = 0.33–0.94). Moreover, the C allele of MMP9-1562C/T could increase serum level of NSCLC in compared with the A allele (OR = 1.19, 95% CI = 0.75–1.89). Similarly, the AA genotype of MMP13 might be a marker of decreased serum level of lung cancer (OR = 0.76, 95% CI = 0.51–1.14). Conclusions: The results of these analyses underline the support of the notion that the CC genotype of MMP9-1562C/T and GG genotypes of MMP13-77G/A were associated with the increased risk NSCLC, and the serum levels of MMP9 and MMP13 were consistent with the results of the SNP analysis. MMP13 and MMP9 might be function as a key oncogene in NSCLC with a Southern Chinese population. Combined detection of SNP and enzyme activity between MMP9 and MMP13 are expected to be a potential diagnostic method of non-small cell lung cancer.

• MMP13
• MMP9
• non-small cell lung cancer
• single-nucleotide polymorphism

Metastasis and invasion are the primary causes of malignant progression in esophageal squamous cell carcinoma (ESCC). Epithelial‐mesenchymal transition (EMT) is crucial step of acquisition of "stemness" properties in tumor cells. However, the mechanism of esophageal cancer metastasis remains unclear. This research was designed to explore the role and mechanism of SMAD4 and miR‐130a‐3p in the progression of transforming growth factor‐β (TGF‐β)‐induced EMT in vivo and in vitro. The expression of miR‐130a‐3p in ESCC cell line and normal esophageal epithelial cell was determined by RT‐qPCR. The protein expression levels of TGF‐β‐induced changes in EMT were analyzed by western blotting and immunofluorescence. Dual‐luciferase report assays were used to validate the regulation of miR‐130a‐3p‐SMAD4 axis. The effect of miR‐130a‐3p and SMAD4 in TGF‐β‐induced migration, invasion in the ESCC cell line EC‐1 was investigated by wound healing assays and Transwell assays. Here we found that knocked down SMAD4 could partially reverse TGF‐β‐induced migration, invasion, and EMT progression in the ESCC cell line EC‐1. miR‐130a‐3p, which directly targets SMAD4, is down‐regulated in ESCC. miR‐130a‐3p inhibits the migration and invasion of EC‐1 cells both in vitro and in vivo. Finally, miR‐130a‐3p inhibits TGF‐β‐induced EC‐1 cell migration, invasion, and EMT progression in a SMAD4‐dependent way. In conclusion, this study provides new insights into the mechanism underlying ESCC metastasis. The TGF‐β/miR‐130a‐3p/SMAD4 pathway could be potential targets for clinical treatment of ESCC.

• Epithelial-mesenchymal transition (EMT)
• Esophageal squamous cell carcinoma (ESCC)
• SMAD4
• transforming growth factor-β (TGF-β)

• Alpha-fetoprotein
• Hepatocellular carcinoma
• Matrix metalloproteinase-12
• Tumor markers

• aurora kinases
• esophageal cancer
• mitosis
• targeted therapy

Epithelial–mesenchymal transition (EMT) is thought to be a crucial event during the early metastasis of tumor cells. Transforming growth factor (TGF)-β1 is involved in the process of EMT in a variety of human malignancies. Matrix metalloproteinase (MMP)-9 plays an important role in tumor invasion and metastasis, and its expression is regulated by various growth factors, including TGF-β1, in different cell types. To date, the role of MMP-9 in TGF-β1-induced EMT in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we aimed to elucidate the mechanism underlying MMP-9-mediated TGF-β1 induction of EMT in ESCC. We analyzed the expression of MMP-9, E-cadherin, and vimentin, in ESCC cells (EC-1), before and after the treatment with exogenous TGF-β1 or a broad spectrum MMP inhibitor, GM6001. Additionally, we analyzed the activity of MMP-9 in these cells and performed MMP-9 knockdown experiments. The results obtained in this study demonstrated that the treatment of EC-1 cells with TGF-β1 can induce EMT, together with the upregulation of vimentin and downregulation of E-cadherin expression in a time-dependent manner. The treatment with GM6001 was shown to attenuate TGF-β1-induced EMT. Furthermore, the exposure of EC-1 cells to TGF-β1 increased the expression and activity of MMP-9, while MMP-9 knockdown blocked TGF-β1-induced EMT and inhibited cell invasiveness and migration. Additionally, treatment with the recombinant human MMP-9 was shown to induce EMT and enhance ESCC cell invasion and metastasis. The obtained data suggest that the regulation of MMP-9 by TGF-β1 may represent a novel mechanism underlying TGF-β1-induced EMT in ESCC.

• epithelial–mesenchymal transition
• esophageal squamous cell carcinoma
• matrix metalloproteinase-9
• transforming growth factor-β1

Background. Matrix metalloproteinases (MMPs) are considered to play an important role during tissue remodeling and extracellular matrix degradation. And functional polymorphisms in MMPs genes have been reported to be associated with the increased risk of periodontitis. Recently, many studies have investigated the association between MMPs polymorphisms and periodontitis risk. However, the results remain inconclusive. In order to quantify the influence of MMPs polymorphisms on the susceptibility to periodontitis, we performed a meta-analysis and systematic review. Results. Overall, this comprehensive meta-analysis included a total of 17 related studies, including 2399 cases and 2002 healthy control subjects. Our results revealed that although studies of the association between MMP-8 −799 C/T variant and the susceptibility to periodontitis have not yielded consistent results, MMP-1 (−1607 1G/2G, −519 A/G, and −422 A/T), MMP-2 (−1575 G/A, −1306 C/T, −790 T/G, and −735 C/T), MMP-3 (−1171 5A/6A), MMP-8 (−381 A/G and +17 C/G), MMP-9 (−1562 C/T and +279 R/Q), and MMP-12 (−357 Asn/Ser), as well as MMP-13 (−77 A/G, 11A/12A) SNPs are not related to periodontitis risk. Conclusions. No association of these common MMPs variants with the susceptibility to periodontitis was found; however, further larger-scale and multiethnic genetic studies on this topic are expected to be conducted to validate our results.

• esophagus squamous cell carcinoma
• matrix metalloproteinase
• single nucleotide polymorphism

Many studies have reported the association between the matrix metalloproteinase (MMP) polymorphisms and lung cancer susceptibility, but the results were inconclusive. We conducted a meta-analysis, using a comprehensive strategy based on the logistic regression and a model-free approach, to derive a more precise estimation of the relationship between MMP1, MMP2, MMP9 and MMP13 polymorphisms with lung cancer risk. A total of 22 case-control studies including 8202 cases and 7578 controls were included in this meta-analysis. For MMP1-1607 1G/2G, increased lung cancer risk was found among Asians in additive model(OR = 1.34, 95%CI:1.18-1.53) and with model-free approach(OR_G = 1.41, 95%CI:1.21-1.65). For MMP2-1306 C/T and -735 C/T, based on the model-free approach, a significantly reduced risk was found in Asians(MMP2-1306 C/T:OR_G = 0.49,95%CI:0.42-0.57; MMP2-735 C/T: OR_G = 0.71, 95%CI:0.61-0.84). For MMP9-1562 C/T, a significantly increased risk was found among Asians(OR = 2.73, 95%CI:1.74-4.27) with model-free approach. For MMP13-77A/G, there was no association between this polymorphism and lung cancer risk in the recessive model(OR = 1.02, 95%CI:0.83-1.26) and with the model-free approach(OR_G = 0.95, 95%CI:0.76-1.17). Therefore, this meta-analysis suggests that the MMP1-1607 1G/2G, MMP2-1306 C/T, MMP2-735 C/T, MMP9 -1562 C/T polymorphisms were risk factors for lung cancer among Asians, while MMP13 -77A/G polymorphism was not associated with lung cancer risk.

Recently, the published data on the association between matrix metalloproteinase-2 (MMP-2) (C-1306T) polymorphism and colorectal cancer (CRC) and gastric cancer (GC) (gastrointestinal cancer) risk remained controversial. The aim of this study is to investigate the relationship between the risk of CRC and GC and single-nucleotide polymorphism of MMP-2(C-1306T).

Medline, Embase, Science Citation Index, and PubMed were thoroughly searched to identify relevant studies. Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association.

We performed a meta-analysis of 14 studies including 642 cases and 692 controls for CRC and 1,936 cases and 3,490 controls for GC. The result indicates that there is significant relationship between MMP-2(C-1306T) polymorphism and CRC risk in recessive model and codominant model (TT vs CC/CT: OR: 2.39, 95% CI: 1.30–4.37, P=0.005; TT vs CC: OR: 2.36, 95% CI: 1.29–4.34, P=0.006). In subgroup analysis according to ethnicity, significant associations were found in Caucasians (TT vs CC/CT: OR: 2.87, 95% CI: 1.43–5.78, P=0.003; TT vs CC: OR: 2.86, 95% CI: 1.41–5.80, P=0.003), but we did not find significant evidence with GC in all genetic models, and in stratified analysis according to ethnicity, no significant risk was found in the subgroup too.

This meta-analysis considered that the MMP-2(C-1306T) polymorphism is a risk factor for CRC susceptibility, especially in Caucasians, but it does not support any relationship to GC, and further studies are needed to explore the association.

• colorectal cancer
• gastric cancer
• matrix metalloproteinase-2

Matrix metalloproteinases (MMPs) are a family of highly homologous extracellular Zn²⁺-dependent endopeptidases, also known as matrixins. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are considered to play a key role in a variety of physiological processes as well as in the development and progression of a vast majority of pathological conditions. Most of the genes encoding MMPs, including MMP-2, are highly polymorphic. One of the single nucleotide polymorphisms with functional activity in the promoter region of MMP2 is the transition MMP2 −1306C>T (rs243865). The aim of the present study was to evaluate the genotype and allele frequencies of the common promoter polymorphism −1306C>T in MMP2 in 75 individuals from central Bulgaria and to compare our results with those of other population studies. We found that 76.0% of the randomly enrolled individuals are carriers of the CC genotype, 17.3% of CT, and 6.7% of the TT genotype. The minor allele frequency (MAF) was 15.3%. Interestingly, the obtained genotype frequencies appeared to differ from those of some other Caucasian populations (USA – 55/38/7, MAF 26%; The Netherlands – 52.8/40.5/6.7, MAF 26.9%; Austria – 55.6/35.5/8.9, MAF 27.2%), but were closer to the values of the reported global genotype distribution (75.3/21.3/3.4, MAF 14%).

• MAF
• MMP2
• SNP
• genotyping

Carcinogenesis is a multistep and also a multifactorial process that involves agents like genetic and environmental factors. Matrix metalloproteinases (MMPs) are major proteolytic enzymes which are involved in cancer cell migration, invasion, and metastasis. Genetic variations in genes encoding the MMPs were shown in human studies to influence cancer risk and phenotypic features of a tumor. The complex role of MMPs seems to be important in the mechanism of carcinogenesis, but it is not well recognized. Rodent studies concentrated particularly on the better understanding of the biological functions of the MMPs and their impact on the pathological process, also through the modification of Mmp genes. This review presents current knowledge and the existing evidence on the importance of selected MMPs in genetic mouse models of cancer and human genetic association studies. Further, this work can be useful for scientists studying the role of the genetic impact of MMPs in carcinogenesis.

• Animals
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Disease Models, Animal
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Matrix Metalloproteinases/physiology
• Mice, Knockout
• Neoplasms/enzymology
• Neoplasms/genetics

AIM: To explore the correlation between the matrix metalloproteinase-2 (MMP-2) gene promoter single nucleotide polymorphism C-1306T (rs243865) and susceptibility to gastric cancer (GC).

METHODS: A computer search of MEDLINE (1966-2013), the Cochrance Library Database (Issue 12, 2013), EMBASE(1980-2013), CINAHL (1982-2013), Web of Science (1945-2013), Chinese Biomedical Literature Database (CBM) (1982-2013), Wanfang (1998-2013) and CNKI (1915-2013) was performed to retrieve relevant studies. Meta-analysis was performed using STATA12.0 statistical software. Risk ratio (RR) and 95% confidence interval (CI) were calculated.

RESULTS: Seven independent case-control studies with a total of 1687 GC patients and 2253 healthy subjects met the inclusion criteria. The findings of the meta-analysis demonstrated that MMP-2 C-1306T polymorphism may be significantly associated with an increased risk of GC [allele model: RR = (1.05, 95%CI: 1.03-1.08), P < 0.001; dominant model: RR = (1.01, 95%CI: 1.00-1.02), P = 0.046]. Results of subgroup analysis by ethnicity showed a significant positive correlation between MMP-2 C-1306T polymorphism and GC risk among Asians [RR = (1.06, 95%CI: 1.04-1.08), P < 0.001], but not among Caucasians (P > 0.05). Further subgroup analyses according to the detection method, genotype, and sample size found that there were significant correlations (P < 0.05 for all) between them in most subgroups.

CONCLUSION: Our findings confirm the hypothesis that MMP-2 C-1306T polymorphism may contribute to an increased risk of GC, especially among Asian populations.

• MMP-2
• Single nucleotide polymorphism
• Gastric cancer
• Meta-analysis

The process of carcinogenesis is tightly regulated by antioxidant enzymes and matrix degrading enzymes, namely, matrix metalloproteinases (MMPs). Degradation of extracellular matrix (ECM) proteins like collagen, proteoglycan, laminin, elastin and fibronectin is considered to be the prerequisite for tumor invasion and metastasis. MMPs can degrade essentially all of the ECM components and, most MMPs also substantially contribute to angiogenesis, differentiation, proliferation and apoptosis. Hence, MMPs are important regulators of tumor growth both at the primary site and in distant metastases; thus the enzymes are considered as important targets for cancer therapy. The implications of MMPs in cancers are no longer mysterious; however, the mechanism of action is yet to be explained. Herein, our major interest is to clarify how MMPs are tied up with gastrointestinal cancers. Gastrointestinal cancer is a variety of cancer types, including the cancers of gastrointestinal tract and organs, i.e., esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus. The activity of MMPs is regulated by its endogenous inhibitor tissue inhibitor of metalloproteinase (TIMP) which bind MMPs with a 1:1 stoichiometry. In addition, RECK (reversion including cysteine-rich protein with kazal motifs) is a membrane bound glycoprotein that inhibits MMP-2, -9 and -14. Moreover, α2-macroglobulin mediates the uptake of several MMPs thereby inhibit their activity. Cancerous conditions increase intrinsic reactive oxygen species (ROS) through mitochondrial dysfunction leading to altered protease/anti-protease balance. ROS, an index of oxidative stress is also involved in tumorigenesis by activation of different MAP kinase pathways including MMP induction. Oxidative stress is involved in cancer by changing the activity and expression of regulatory proteins especially MMPs. Epidemiological studies have shown that high intake of fruits that rich in antioxidants is associated with a lower cancer incidence. Evidence indicates that some antioxidants inhibit the growth of malignant cells by inducing apoptosis and inhibiting the activity of MMPs. This review is discussed in six subchapters, as follows.

• Gastrointestinal cancer
• Matrix metalloproteinase
• Tissue inhibitor of matrix metalloproteinases
• Reactive oxygen species
• Antioxidants

• E3 ubiquitin protein ligase (MDM2) gene
• MDM2 oncogene
• Oesophageal cancer
• gastric cancer
• meta-analysis
• polymorphism
• susceptibility

• Humans
• Digestive System Neoplasms/etiology
• Matrix Metalloproteinases/genetics
• Polymorphism, Genetic/genetics
• Promoter Regions, Genetic/genetics
• Risk Factors

• Drug targets therapy
• Hematological malignancies
• MMPs
• Polymorphism and solid cancer
• SNPs

• Cervical cancer
• Matrix metalloproteinase
• Susceptibility
• Tissue inhibitor of metalloproteinase

• Adult
• Female
• Gallbladder Neoplasms/epidemiology
• Gallbladder Neoplasms/genetics
• Genetic Predisposition to Disease/epidemiology
• Genetic Predisposition to Disease/genetics
• Genetic Variation
• Haplotypes
• Humans
• India/epidemiology
• Logistic Models
• Male
• Matrix Metalloproteinase 2/genetics
• Matrix Metalloproteinase 7/genetics
• Matrix Metalloproteinase 9/chemistry
• Matrix Metalloproteinase 9/genetics
• Middle Aged
• Models, Chemical
• Multivariate Analysis
• Polymorphism, Genetic
• Risk Factors
• Tissue Inhibitor of Metalloproteinase-2/genetics

• Blotting, Western
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/physiopathology
• Cell Line, Tumor
• China
• DNA Primers/genetics
• Esophageal Neoplasms/metabolism
• Esophageal Neoplasms/physiopathology
• Gene Expression Regulation, Neoplastic/physiology
• HMGA2 Protein/metabolism
• Humans
• Immunohistochemistry
• MicroRNAs/metabolism
• Real-Time Polymerase Chain Reaction
• Statistics, Nonparametric
• Transfection

Matrix metalloproteinases (MMPs) are implicated in cancer development and progression and are associated with prognosis. Single-nucleotide polymorphisms (SNPs) of MMPs, most frequently located in the promoter region of the genes, have been shown to influence cancer susceptibility and/or progression. SNPs of MMP-1, -2, -3, -7, -8, -9, -12, -13 and -21 and of the tissue inhibitor of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 have been studied in digestive tract tumors. The contribution of these polymorphisms to the cancer risk and prognosis of gastrointestinal tumors are reviewed in this paper.

• Matrix metalloproteinase
• Tissue inhibitor of metalloproteinase
• Single nucleotide polymorphism
• Promoter region
• Digestive tract
• cancer

• Base Sequence
• Butadienes/pharmacology
• Dose-Response Relationship, Drug
• Enzyme Activation
• Enzyme Inhibitors/pharmacology
• Esophageal Neoplasms/metabolism
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Gene Expression Profiling
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• MAP Kinase Signaling System
• Molecular Sequence Data
• Nitriles/pharmacology
• Phosphorylation
• Signal Transduction

Esophageal adenocarcinomas (EACs) arise due to gastroesophageal reflux, with Barrett's esophagus (BE) regarded as precancerous lesion. Matrix metalloproteinases (MMPs) might play a role during the multistep carcinogenetic process.

Expression of MMP-1 and -13 was analyzed in esophageal cancer (n = 41 EAC with BE, n = 19 EAC without BE, and n = 10 esophageal squamous-cell carcinomas, ESCC), furthermore in BE without intraepithelial neoplasia (IN) (n = 18), and the cell line OE-33. MMP-1 was co-labelled with Ki-67 (proliferation), Cdx-2 (marker for intestinal metaplasia, BE) and analyzed on mRNA level. MMP-1 staining results were correlated with clinicopatholocical parameters.

On protein level, MMP-1 expression was found in 39 of 41 (95%) EAC with BE, in 19 of 19 (100%) EAC without BE, in 6 of 10 (60%) ESCC, and in 10 of 18 (56%) BE without IN. No expression of MMP-13 was found in these specimens. Quantification showed 48% MMP-1 positive cells in EAC with BE, compared to 35% in adjacent BE (p < 0.05), 44% in EAC without BE, 32% in ESCC, and 4% in BE without IN. Immunofluorescence double staining experiments revealed increased MMP-1 expressing in proliferating cells (MMP-1+/Ki-67+) (r = 0.943 for BE and r = 0.811 for EAC). On mRNA-level, expression of MMP-1 was significantly higher in EAC compared to BE (p = 0.01) and confirmed immunohistochemical staining results. High MMP-1 levels were associated with lymph node metastases but not with poorer survival (p = 0.307).

Our findings suggest that MMP-1 plays a role as preinvasive factor in BE-associated EAC. Expression of MMP-1 in proliferating BE and EAC cells suggest malignant proliferation following the clonal expansion model.