• COPD
• Cancer
• Drug designing
• MMP-12
• MMP-12 inhibitor

• Animals
• Humans
• Drug Design
• Matrix Metalloproteinase 12/metabolism
• Matrix Metalloproteinase 12/chemistry
• Matrix Metalloproteinase Inhibitors/pharmacology
• Matrix Metalloproteinase Inhibitors/chemistry
• Matrix Metalloproteinase Inhibitors/chemical synthesis
• Molecular Structure
• Neoplasms/drug therapy
• Neoplasms/pathology
• Structure-Activity Relationship
• Zinc/chemistry

• anticancer activity
• extra-cellular matrix remodeling
• inhibitors
• matrix metalloproteinases (MMPs)

• MMP-3
• association
• cancer
• correlation
• matrix metalloproteinase-3
• meta-analysis
• polymorphism
• susceptibility
• trial sequential analysis
• variants

• Female
• Humans
• Breast Neoplasms
• Case-Control Studies
• Esophageal Neoplasms/genetics
• Genetic Predisposition to Disease
• Matrix Metalloproteinase 3/genetics
• Polymorphism, Genetic
• Polymorphism, Single Nucleotide

Bioinformatics methods are used to construct an immune gene prognosis assessment model for patients with non-small cell lung cancer (NSCLC), and to screen biomarkers that affect the occurrence and prognosis of NSCLC. The transcriptomic data and clinicopathological data of NSCLC and cancer-adjacent normal tissues were downloaded from the Cancer Genome Atlas (TCGA) database and the immune-related genes were obtained from the IMMPORT database (http://www.immport.org/); then, the differentially expressed immune genes were screened out. Based on these genes, an immune gene prognosis model was constructed. The Cox proportional hazards regression model was used for univariate and multivariate analyses. Further, the correlations among the risk score, clinicopathological characteristics, tumor microenvironment, and the prognosis of NSCLC were analyzed. A total of 193 differentially expressed immune genes related to NSCLC were screened based on the "wilcox.test" in R language, and Cox single factor analysis showed that 19 differentially expressed immune genes were associated with the prognosis of NSCLC (P < 0.05). After including 19 differentially expressed immune genes with P < 0.05 into the Cox multivariate analysis, an immune gene prognosis model of NSCLC was constructed (it included 13 differentially expressed immune genes). Based on the risk score, the samples were divided into the high-risk and low-risk groups. The Kaplan–Meier survival curve results showed that the 5-year overall survival rate in the high-risk group was 32.4%, and the 5-year overall survival rate in the low-risk group was 53.7%. The receiver operating characteristic model curve confirmed that the prediction model had a certain accuracy (AUC = 0.673). After incorporating multiple variables into the Cox regression analysis, the results showed that the immune gene prognostic risk score was an independent predictor of the prognosis of NSCLC patients. There was a certain correlation between the risk score and degree of neutrophil infiltration in the tumor microenvironment. The NSCLC immune gene prognosis assessment model was constructed based on bioinformatics methods, and it can be used to calculate the prognostic risk score of NSCLC patients. Further, this model is expected to provide help for clinical judgment of the prognosis of NSCLC patients.

• 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

• Cell growth
• Dysfunction module
• Human nasopharyngeal carcinoma
• Regulatory factors
• Signaling pathway

In the last years, the extracellular matrix (ECM) has been reported as playing a relevant role in esophageal cancer (EC) development, with this compartment being related to several aspects of EC genesis and progression. This sounds very interesting due to the complexity of this highly incident and lethal tumor, which takes the sixth position in mortality among all tumor types worldwide. The well-established increase in ECM stiffness, which is able to trigger mechanotransduction signaling, is capable of regulating several malignant behaviors by converting alteration in ECM mechanics into cytoplasmatic biochemical signals. In this sense, it has been shown that some molecules play a key role in these events, particularly the different collagen isoforms, as well as enzymes related to its turnover, such as lysyl oxidase (LOX) and matrix metalloproteinases (MMPs). In fact, MMPs are not only involved in ECM stiffness, but also in other events related to ECM homeostasis, which includes ECM remodeling. Therefore, the crucial role of distinct MMPs isoform has already been reported, especially MMP-2, -3, -7, and -9, along EC development, thus strongly associating these proteins with the control of important cellular events during tumor progression, particularly in the process of invasion during metastasis establishment. In addition, by distinct mechanisms, a vast diversity of glycoproteins and proteoglycans, such as laminin, fibronectin, tenascin C, galectin, dermatan sulfate, and hyaluronic acid exert remarkable effects in esophageal malignant cells due to the activation of oncogenic signaling pathways mainly involved in cytoskeleton alterations during adhesion and migration processes. Finally, the wide spectrum of interactions potentially mediated by ECM may represent a singular intervention scenario in esophageal carcinogenesis natural history and, due to the scarce knowledge on the cellular and molecular mechanisms involved in EC development, the growing body of evidence on ECM’s role along esophageal carcinogenesis might provide a solid base to improve its management in the future.

• adhesion
• esophageal carcinogenesis
• extracellular matrix
• glycoproteins
• metalloproteinases
• proteoglycans
• remodeling
• stiffness

Background: MicroRNAs (miRNAs) play a key role in the development of gastric cancer (GC). MiRNA arrays showed that lymph node metastasis in GC is correlated with the expression of miR-1284. Although its function and mechanisms in GC have not been fully described, the regulation of EIF4A1 by miR-1284 and its role in drug-resistant GC has been reported in our previous studies.

Methods: qRT-PCR was used to study the level of miR-1284 expression in GC cell lines and tissues. Subsequently, the CCK-8 assay was used to detect cell proliferation, while transwell assay was used to detect invasion and migration of the GC cells. Flow cytometry was used to detect the effect of miR-1284 on GC cells in vivo by building subcutaneous GC nude mice transplantation tumor model. In addition, the influence of miR-1284 gene expression profile in SGC-7901 cells was detected by total gene expression chip, and the target gene of miR-1284 was detected by luciferase reporter assay, qRT-PCR, and western blotting.

Results: The miR-1284 level was down-regulated in GC tssues and cell lines. MiR-1284 was significantly associated with tumor size, degree of differentiation and patients’ distant metastasis. MiR-1284 inhibited invasion, migration, and proliferation of GC cells. During the G1/S phase, miR-1284 arrested the cycle of GC cells in vitro. MiR-1284 also suppressed tumor from growing and metastasizing in xenograft models as well as influenced the gene expression profile in SGC-7901 cells. Also, EIF4A1 was the direct target gene for miR-1284. Further, an inverse correlation between the miR-1284 expression and EIF4A1 was found in GC tissues. Over-expressed miR-1284 decreased c-Myc, MMP12, JUN expression, while increased CDH1 expression.

Conclusion: These data suggested that miR-1284 acts as a tumor suppressor, and directly blocked EIF4A1 in GC.

• EIF4A1
• MiR-1284
• gastric cancer
• metastasis
• proliferation

• Gene polymorphism
• MMP-3
• Pelvic organ prolapse
• Risk factors

• JUN pathway
• MST4
• gastric cancer
• miR-593-5p

• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Biomarkers, Tumor/metabolism
• Esophageal Neoplasms/metabolism
• Esophageal Neoplasms/pathology
• Humans
• Prognosis
• Proportional Hazards Models
• Survival Analysis

• Allele frequency
• Extracellular matrix
• Susceptibility

• ALDH2
• Han
• Kazak
• c12orf30
• esophageal squamous cell carcinoma
• gene polymorphism
• prognosis
• susceptibility

• MMP12
• growth
• invasion
• lung adenocarcinoma

• ALDH1A2
• BARX1
• Barrett’s esophagus
• Esophageal adenocarcinoma
• FOXF1
• FOXP1
• GFD7
• GWAS
• TBX5
• chr6p21

• Adenocarcinoma/diagnosis
• Adenocarcinoma/genetics
• Barrett Esophagus/diagnosis
• Barrett Esophagus/genetics
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/pathology
• Disease Progression
• Esophageal Neoplasms/diagnosis
• Esophageal Neoplasms/genetics
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease/genetics
• Genetic Variation
• Genome-Wide Association Study/methods
• Humans

• 16459 Cancer Research UK

• Barrett’s esophagus
• Biomarkers
• Esophageal cancer
• Esophageal dysplasia
• Genetic

• Adenocarcinoma/diagnosis
• Adenocarcinoma/genetics
• Barrett Esophagus/diagnosis
• Barrett Esophagus/genetics
• Barrett Esophagus/therapy
• Disease Progression
• Esophageal Neoplasms/diagnosis
• Esophageal Neoplasms/genetics
• Esophagus/pathology
• Genetic Markers
• Genetic Predisposition to Disease
• Genetic Variation
• Genome-Wide Association Study
• Humans
• Phenotype
• Precancerous Conditions/diagnosis
• Precancerous Conditions/genetics
• Precancerous Conditions/therapy
• Prognosis
• Risk Assessment
• Risk Factors
• Treatment Outcome

• 16459 Cancer Research UK
• 090532/Z/09/Z Wellcome Trust
• Wellcome Trust (GB)

Barrett’s oesophagus (BO) is a common condition, predisposing strongly to the development of oesophageal adenocarcinoma (OAC). Consequently, there has been considerable effort to determine the processes involved in the development of BO metaplasia, and ultimately develop markers of patients at risk. Whilst a number of robust acquired risk factors have been identified, a genetic component to these and the apparent increased susceptibility of certain individuals has long been suspected. This has been evidenced in part by linkage studies, but subsequently two recent genome-wide association studies (GWAS) have suggested mechanisms underlying the heritability of BO, as well as providing the first direct evidence at modern levels of statistical significance. This review discusses BO heritability, in addition to that of individual variants and genes reported to be associated with BO to date. Through this, we identify a number of plausible associations, although often tempered by issues of methodology, and discuss the priorities and need for future research.

• Barrett’s oesophagus
• biomarkers
• genetic susceptibility
• genetics
• oesophageal adenocarcinoma

• MMP-12
• single nucleotide polymorphism
• tumor susceptibility

• Case-Control Studies
• Genetic Predisposition to Disease
• Humans
• Matrix Metalloproteinase 1/genetics
• Neoplasms/etiology
• Neoplasms/genetics
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Risk
• Risk Factors

• Cancer
• MMP1
• genetics
• 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

Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas.

569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression).

Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p = 0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6^th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p = 0.001) and 7^th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p = 0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact.

The MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6^th or 7^th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome.

• 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

• lung cancer
• case–control
• survival
• chronic bronchitis
• emphysema
• matrix metalloproteinase-1
• gene polymorphism
• rs11292517

• Black or African American/genetics
• Aged
• Carcinoma, Non-Small-Cell Lung/enzymology
• Carcinoma, Non-Small-Cell Lung/ethnology
• Carcinoma, Non-Small-Cell Lung/genetics
• Case-Control Studies
• Cohort Studies
• Female
• Genetic Predisposition to Disease
• Humans
• Lung Neoplasms/enzymology
• Lung Neoplasms/ethnology
• Lung Neoplasms/genetics
• Male
• Matrix Metalloproteinase 1/genetics
• Middle Aged
• Polymorphism, Genetic
• Pulmonary Disease, Chronic Obstructive/enzymology
• Pulmonary Disease, Chronic Obstructive/ethnology
• Pulmonary Disease, Chronic Obstructive/genetics
• White People/genetics

• T32 ES007141 NIEHS NIH HHS
• Intramural NIH HHS
• ES 07141 NIEHS NIH HHS

Degradation of the extracellular matrix is fundamental to tumour development, invasion and metastasis. Several protease families have been implicated in the development of a broad range of tumour types, including oesophago–gastric (OG) adenocarcinoma. The aim of this study was to analyse the expression levels of all core members of the cancer degradome in OG adenocarcinoma and to investigate the relationship between expression levels and tumour/patient variables associated with poor prognosis.

Comprehensive expression profiling of the protease families (matrix metalloproteinases (MMPs), members of the ADAM metalloproteinase-disintegrin family (ADAMs)), their inhibitors (tissue inhibitors of metalloproteinase), and molecules involved in the c-Met signalling pathway, was performed using quantitative real-time reverse transcription polymerase chain reaction in a cohort of matched malignant and benign peri-tumoural OG tissue (n=25 patients). Data were analysed with respect to clinico-pathological variables (tumour stage and grade, age, sex and pre-operative plasma C-reactive protein level).

Gene expression of MMP1, 3, 7, 9, 10, 11, 12, 16 and 24 was upregulated by factors >4-fold in OG adenocarcinoma samples compared with matched benign tissue (P<0.01). Expression of ADAM8 and ADAM15 correlated significantly with tumour stage (P=0.048 and P=0.044), and ADAM12 expression correlated with tumour grade (P=0.011).

This study represents the first comprehensive quantitative analysis of the expression of proteases and their inhibitors in human OG adenocarcinoma. These findings implicate elevated ADAM8, 12 and 15 mRNA expression as potential prognostic molecular markers.

Matrix metalloproteases (MMPs) are proteolytic enzymes that contribute to all stages of tumour progression, including the later stages of invasion and metastasis. Genetic variants in the MMP genes may influence the biological function of these enzymes and change their role in carcinogenesis and progression. We have investigated the association between the -735 C/T, the -1171 5A/6A, and the -1562 C/T polymorphisms in the MMP2, MMP3 and MMP9 genes, respectively, and the risk and survival of lung cancer.

The case-control study includes 879 lung cancer patients and 803 controls from a Caucasian population in Spain (CAPUA study). Genotypes were determined by PCR-RFLP. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression. The Kaplan-Meier method, long-rank test and Cox's were used for the survival analysis.

The MMP9 -1562 T/T genotype was associated with a statistically significant decreased risk of developing lung cancer (OR = 0.23; 95% CI: 0.06-0.85), whereas no association was found for the MMP2 -735 C/T and MMP3 -1171 5A/6A polymorphisms. The MMP2 -735 T/T genotype was statistically significantly associated with a decreased survival in non-small cell lung cancer (NSCLC) patients, identified as an independent prognosis factor of survival (hazard ratio (HR) = 1.79; 95% CI: 1.00-3.20). In contrast, no association was found between the MMP3 -1171 5A/6A and the MMP9 -1562 C/T polymorphisms and survival.

These findings support the hypothesis that the MMP9 -1562 C/T polymorphism is associated with a protective effect against the development of lung cancer and suggest that the MMP2 -735 C/T polymorphism modify the length of survival in NSCLC patients.

• esophageal adenocarcinoma
• angiogenesis pathway genes
• gene-environment interaction
• case-only analysis

• Adenocarcinoma/etiology
• Angiogenic Proteins/genetics
• Body Mass Index
• DNA, Neoplasm/genetics
• Esophageal Neoplasms/etiology
• Female
• Gastroesophageal Reflux/etiology
• Gene-Environment Interaction
• Humans
• Logistic Models
• Male
• Middle Aged
• Polymerase Chain Reaction
• Polymorphism, Single Nucleotide/genetics
• Prognosis
• Risk Factors
• Signal Transduction
• Smoking

• P20 CA090578 NCI NIH HHS
• CA119650 NCI NIH HHS
• R03 CA110822 NCI NIH HHS
• R01 CA074386 NCI NIH HHS
• R01 CA109193 NCI NIH HHS
• CA74386 NCI NIH HHS
• CA90578 NCI NIH HHS
• CA92824 NCI NIH HHS
• P50 CA090578 NCI NIH HHS
• P01 CA134294 NCI NIH HHS
• R03 CA119650 NCI NIH HHS
• R01 CA092824 NCI NIH HHS
• R35 CA197449 NCI NIH HHS

• Case-Control Studies
• Disease Progression
• Female
• Genetic Predisposition to Disease
• Humans
• Lung Neoplasms/genetics
• Male
• Matrix Metalloproteinase 1/genetics
• Meta-Analysis as Topic
• Middle Aged
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Risk

• cholestasis
• genetics
• genomics
• liver
• psc

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Case-Control Studies
• Child
• Cholangitis, Sclerosing/enzymology
• Cholangitis, Sclerosing/genetics
• Cholangitis, Sclerosing/mortality
• Colitis, Ulcerative/epidemiology
• Comorbidity
• Disease Progression
• Female
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease
• Haplotypes
• Humans
• Kaplan-Meier Estimate
• Linkage Disequilibrium
• Logistic Models
• Male
• Matrix Metalloproteinase 3/genetics
• Middle Aged
• Minnesota
• Phenotype
• Polymorphism, Single Nucleotide
• Proportional Hazards Models
• Risk Assessment
• Risk Factors
• Young Adult

• R01 DK084960 NIDDK NIH HHS
• R01DK084960 NIDDK NIH HHS

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

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.