• ATP
• Caco-2 cells
• Colorectal cancer
• HuR
• P2R

• Humans
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Adenosine Triphosphate/metabolism
• ELAV-Like Protein 1/metabolism
• Caco-2 Cells
• Disease Progression
• Active Transport, Cell Nucleus/drug effects
• Cell Proliferation/drug effects
• Receptors, Purinergic/metabolism

• Al-Azhar University

• GPR124
• RECK
• WNT7
• gastric cancer
• pancreatic cancer

• Humans
• GPI-Linked Proteins/metabolism
• GPI-Linked Proteins/genetics
• Receptors, G-Protein-Coupled/metabolism
• Receptors, G-Protein-Coupled/genetics
• Pancreatic Neoplasms/metabolism
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/genetics
• Wnt Signaling Pathway
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Stomach Neoplasms/genetics
• Cell Line, Tumor
• Cell Proliferation
• Carcinoma, Pancreatic Ductal/metabolism
• Carcinoma, Pancreatic Ductal/pathology
• Carcinoma, Pancreatic Ductal/genetics
• Wnt Proteins/metabolism
• HEK293 Cells
• Apoptosis
• Receptors, Estrogen

• 19K22555 Japan Society for the Promotion of Science
• 20H03509 Japan Society for the Promotion of Science
• Japan Society for the Promotion of Science

• Gastric cancer
• Invasion
• Migration
• RECK
• SIAH1
• Ubiquitination

• CALD1
• ERK/MAPK
• Gastric cancer
• RECK
• Tumor suppressor

• Humans
• Stomach Neoplasms/metabolism
• Prognosis
• Cell Line, Tumor
• GPI-Linked Proteins/metabolism
• Signal Transduction
• Gene Expression Regulation, Neoplastic
• Tumor Microenvironment

• National Natural Science Foundation of China
• the Science and Technology Research Project of the Education Department of Jilin Province

• Cancer
• Gastroenterology
• Mouse models
• Oncology
• Tumor suppressors

• Animals
• Humans
• Mice
• Cadherins/genetics
• Carcinoma, Pancreatic Ductal/genetics
• Epithelial-Mesenchymal Transition/genetics
• GPI-Linked Proteins/genetics
• Liver Neoplasms/genetics
• Pancreas
• Pancreatic Neoplasms/genetics

• Hepatitis B virus
• Hepatocellular carcinoma
• RECK gene, polymorphism
• Risk factor

• Carcinoma, Hepatocellular/genetics
• Case-Control Studies
• Child
• GPI-Linked Proteins/genetics
• Genetic Predisposition to Disease
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/complications
• Hepatitis B, Chronic/genetics
• Humans
• Liver Neoplasms/pathology
• Polymorphism, Single Nucleotide
• alpha-Fetoproteins

Colorectal cancer (CRC) is one of the most common cancer worldwide. CRC is derived from polyps and many factors, such as Matrix Metalloproteinases (MMPs) can gain the progression of colorectal carcinogenesis. Many investigations have indicated the role of MMPs in CRC development while there is not enough knowledge about the function of MMPs in precancerous conditions. This review summarizes the current information about the role of MMPs in polyps and CRC progression.

Colorectal cancer (CRC) is the third and second cancer for incidence and mortality worldwide, respectively, and is becoming prevalent in developing countries. Most CRCs derive from polyps, especially adenomatous polyps, which can gradually transform into CRC. The family of Matrix Metalloproteinases (MMPs) plays a critical role in the initiation and progression of CRC. Prominent MMPs, including MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MMP-14, and MMP-21, have been detected in CRC patients, and the expression of most of them correlates with a poor prognosis. Moreover, many studies have explored the inhibition of MMPs and targeted therapy for CRC, but there is not enough information about the role of MMPs in polyp malignancy. In this review, we discuss the role of MMPs in colorectal cancer and its pathogenesis

• MMP polymorphisms
• MMP targeting
• Matrix Metalloproteinases (MMPs)
• TIMPs
• colorectal cancer
• polyp

• HPV
• MMP inhibitors
• RECK
• cervical cancer
• tumorigenesis

• Dog
• Inflammation
• Macrophages
• Mammary tumors
• Tumor microenvironment

• buccal mucosal squamous cell carcinoma
• clinicopathological features
• prognosis
• reversion-inducing cysteine-rich protein with Kazal motifs

• AKT signaling pathway
• Epilepsy
• Hippocampal neurons
• RECK
• microRNA-200c-3p

• RECK
• cervical cancer
• invasion
• migration
• p53

• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• Cricetinae
• GPI-Linked Proteins/chemistry
• GPI-Linked Proteins/genetics
• GPI-Linked Proteins/metabolism
• Gene Expression Regulation, Neoplastic/drug effects
• Hypoxia-Inducible Factor 1, alpha Subunit/chemistry
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Immunohistochemistry
• Limonins/chemistry
• Limonins/pharmacology
• Male
• MicroRNAs/chemistry
• MicroRNAs/genetics
• Neovascularization, Pathologic/genetics
• Neovascularization, Pathologic/metabolism
• RNA Interference
• Signal Transduction/drug effects

Matrix metalloproteinases (MMPs), a family of endopeptidases also known as gelatinases, have been reported to affect the acquisition of the cell proliferative, cell invasive and metastatic phenotype of several types of cancer. In particular, the gelatinases MMP-2 and −9 have been revealed to facilitate tumor growth and invasion in patients with colorectal cancer (CRC). However, it is not known whether the gelatinase activity of MMP-2 and −9 is also elevated in Vietnamese patients with CRC. The activity of MMP-2 and −9 in the tissue samples of 103 patients with CRC was evaluated by gelatin zymography and quantified using ImageJ. The association between the level of activity of MMP-2 and −9 and various clinicopathological factors was analyzed, and Chisio BioPAX Editor software was used to visualize the biological pathways regulating the activity of the MMPs. The present study noticed significantly increased activity of active MMP-2 and MMP-9 in tumor tissues (P<0.01), and significantly decreased levels of pro-form MMP-2 and MMP-9 in tumor tissues (P<0.01), compared with that in adjacent tissues in patients with CRC. A correlation between the normalized different activity of MMP-2 and −9 and various clinicopathological features was observed. Furthermore, bioinformatics analysis indicated that the alteration in the activity of MMP-2 and MMP-9 may have been controlled by biological pathways involving the tissue inhibitors of metalloprotease-2 and −1. These findings indicate that the activity of the gelatinases MMP-2 and −9 affects the tumor progression and metastasis of patients with CRC, providing a potential novel approach for determining the prognosis of CRC.

• MMP-2
• MMP-9
• colorectal cancer
• gelatin zymography

• Anacardic acid
• EMMPRIN
• Gelatinases
• MMP-14
• RECK
• Spry2

• Fibroids
• Myometrium
• RECK
• Uterine leiomyoma
• miR-15b

• Cell Line
• Female
• GPI-Linked Proteins/biosynthesis
• GPI-Linked Proteins/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Leiomyoma/genetics
• Leiomyoma/metabolism
• Leiomyoma/pathology
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• Tumor Cells, Cultured
• Uterine Neoplasms/genetics
• Uterine Neoplasms/metabolism
• Uterine Neoplasms/pathology

• Scientific and Technological Project of Henan Province

Increasing evidence suggests that the dysregulation of certain microRNAs plays an important role in tumorigenesis and metastasis. MiR-200c exhibits a disordered expression in many tumors and presents dual roles in bladder cancer (BC). Therefore, the definite role of miR-200c in BC needs to be investigated further.

Quantitative reverse transcription polymerase chain reaction was used to assess miR-200c expression. Cell invasion and migration were evaluated using wound healing and transwell assays. The luciferase reporter assay was used to identify the direct target of miR-200c. The expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK) in BC tissues and adjacent nontumor tissues, as well as in BC cell lines, was detected through quantitative reverse transcription polymerase chain reaction, Western blot assay, and immunohistochemistry.

The miR-200c expression was significantly upregulated in the BC tissues compared with the adjacent nontumor tissues. The downregulation of miR-200c significantly inhibited cell migration and invasion in the BC cell lines. The luciferase reporter assay showed that RECK was a direct target of miR-200c. The knockdown of RECK in the BC cell lines treated with anti-miR-200c elevated the previously attenuated cell migration and invasion.

Our findings indicated that miR-200c functions as oncogenes in BC and may provide a novel therapeutic strategy for the treatment of BC.

• RECK
• bladder cancer
• invasion
• miR-200c
• migration

AIM: To investigate the expression of integrin αvβ6 and matrix metalloproteinase 9 (MMP-9), their association with prognostic factors and to assess their predictive role in gastric cancer patients.

METHODS: Immunohistochemistry was used to determine the expressions of integrin αvβ6 and MMP-9 in 126 specimens from patients with primary gastric carcinoma. Associations between immunohistochemical staining and various clinic pathologic variables of tissue specimens were evaluated by the χ² test and Fisher’s exact test. Expression correlation of αvβ6 and MMP-9 was assessed using bivariate correlation analysis. The patients were followed-up every 3 mo in the first two years and at least every 6 mo afterwards, with a median follow-up of 56 mo (ranging from 2 mo to 94 mo). Four different combinations of αvβ6 and MMP-9 levels (that is, both markers positive, both markers negative, αvβ6 positive with MMP-9 negative, and αvβ6 negative with MMP-9 positive) were evaluated for their relative effect on survival. The difference in survival curves was evaluated with a log-rank test. Survival analysis was conducted using the Kaplan-Meier survival and Cox proportional hazards model analysis.

RESULTS: The expressions of integrin αvβ6 and MMP-9 were investigated in 126 cases, among which 34.92% were positive for αvβ6 expression, and 42.06% for MMP-9 expression. The expression of αvβ6 was associated with Lauren type, differentiation, N stage, and TNM stage (the P values were 0.006, 0.038, 0.016, and 0.002, respectively). While MMP-9 expression was associated with differentiation, T stage, N stage, and TNM stage (the P values were 0.039, 0.014, 0.033, and 0.008, respectively). The positive correlation between αvβ6 and MMP-9 in gastric cancer was confirmed by a correlation analysis. The Kaplan-Meier survival analysis showed that patients with expression of αvβ6 or MMP-9 alone died earlier than those with negative expression and that patients who were both αvβ6 and MMP-9 positive had a shorter overall survival than those with the opposite pattern (both αvβ6 and MMP-9 negative) (P = 0.000). A Cox model indicated that positive expression of αvβ6 and MMP-9, diffuse Lauren type, as well as a senior grade of N stage, M stage, and TNM stage were predictors of a poor prognosis in univariate analysis. Only αvβ6 and MMP-9 retained their significance when adjustments were made for other known prognostic factors in multivariate analysis (RR = 2.632, P = 0.003 and RR = 1.813, P = 0.007).

CONCLUSION: The expression of αvβ6 and MMP-9 are closely correlated, and the combinational pattern of αvβ6 and MMP-9 can serve as a more effective prognostic index for gastric cancer patients.

• Gastric cancer
• Integrin αvβ6
• Prognosis
• Matrix metalloproteinase 9
• Survival

• Adult
• Aged
• Aged, 80 and over
• Antigens, Neoplasm/analysis
• Biomarkers, Tumor/analysis
• Chi-Square Distribution
• Female
• Humans
• Immunohistochemistry
• Integrins/analysis
• Kaplan-Meier Estimate
• Male
• Matrix Metalloproteinase 9/analysis
• Middle Aged
• Multivariate Analysis
• Neoplasm Staging
• Predictive Value of Tests
• Proportional Hazards Models
• Risk Factors
• Stomach Neoplasms/enzymology
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy
• Time Factors
• Treatment Outcome

The REversion-inducing Cysteine-rich protein with Kazal motif (RECK) is a well-known inhibitor of matrix metalloproteinases (MMPs) and cellular invasion. Although high expression levels of RECK have already been correlated with a better clinical outcome for several tumor types, its main function, as well as its potential prognostic value for breast cancer patients, remain unclear.

The RECK expression profile was investigated in a panel of human breast cell lines with distinct aggressiveness potential. RECK functional analysis was undertaken using RNA interference methodology. RECK protein levels were also analyzed in 1040 cases of breast cancer using immunohistochemistry and tissue microarrays (TMAs). The association between RECK expression and different clinico-pathological parameters, as well as the overall (OS) and disease-free (DFS) survival rates, were evaluated.

Higher RECK protein expression levels were detected in more aggressive breast cancer cell lines (T4-2, MDA-MB-231 and Hs578T) than in non-invasive (MCF-7 and T47D) and non-tumorigenic (S1) cell lines. Indeed, silencing RECK in MDA-MB-231 cells resulted in elevated levels of pro-MMP-9 and increased invasion compared with scrambled (control) cells, without any effect on cell proliferation. Surprisingly, by RECK immunoreactivity analysis on TMAs, we found no association between RECK positivity and survival (OS and DFS) in breast cancer patients. Even considering the different tumor subtypes (luminal A, luminal B, Her2 type and basal-like) or lymph node status, RECK remained ineffective for predicting the disease outcome. Moreover, by multivariate Cox regression analysis, we found that RECK has no prognostic impact for OS and DFS, relative to standard clinical variables.

Although it continues to serve as an invasion and MMP inhibitor in breast cancer, RECK expression analysis is not useful for prognosis of these patients.

Wilms’ tumor (WT) is the most common malignant renal tumor in children. Previous studies suggested the reversion-inducing, cysteine-rich protein with Kazal motifs (RECK) down-regulation might have a role in numerous human cancers. The current study was done to investigate the associations of RECK single-nucleotide polymorphisms (SNPs) with the WT susceptibility in Chinese children.

We analyzed 2 SNPs (rs10972727and rs11788747) in a total of 97 WT children and 194 healthy matched controls (1:2 ratio) by real-time PCR and PCR-RFLP genotyping analysis.

We found that the G allele of rs11788747 in the RECK gene was significantly associated with WT in Chinese children (OR=0.7, 95% CI: 0.45–0.99; P=0.042); as with another SNP rs10972727, however, no statistically significant difference was detected. Further analysis showed there was also a statistically significant difference in genotype frequencies between terminal tumor stage (P=0.026) and metastatic groups (P=0.002).

The present data indicate that there is a significant association between mutant G of rs11788747 in RECK and WT risk. G carriers with advanced tumor stage or with metastasis might have an increased risk of WT.

• Egypt
• HCC
• RECK
• rs 11788747

Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol-anchored glycoprotein, inhibits the enzymatic activities of certain matrix metalloproteinases (MMPs). RECK has been studied in numerous human tumors, but the expression of RECK in salivary adenoid cystic carcinoma (SACC), and its correlation with patient prognosis, has never been investigated thus far. In the present study, the expression of RECK and MMP-2 was evaluated in two ACC cell lines and in 83 patients with SACC. The results of quantitative polymerase chain reaction and western blot analysis revealed that the ACC-2 and ACC-M cell lines expressed RECK and MMP-2 mRNA and protein. The immunohistochemical staining in the patients demonstrated that positive expression of RECK and MMP-2 was observed in 21/83 (25.3%) and 69/83 (83.1%) cases, respectively, and that RECK expression was significantly associated with the tumor-node-metastasis stage, histological grade and perineural invasion of patients with SACC (P<0.05). Furthermore, there was a significant association between the positive expression of RECK and that of MMP-2 (P<0.0001). Univariate and multivariate analyses confirmed that a lack of RECK expression was an independent and significant factor for the prediction of a poor prognosis. In conclusion, RECK is a promising prognostic marker and potential therapeutic agent in SACC.

• MMP-2
• RECK
• adenoid cystic carcinoma
• prognosis

Reversion-inducing cysteine-rich protein with Kazal motifs (RECK, a tumor suppressor) is down-regulated by the oncogenic signals and hypoxia, but the biological function of RECK in early tumorigenic hyperplastic phenotypes is largely unknown. Knockdown of RECK by small interfering RNA (siRECK) or hypoxia significantly promoted cell proliferation in various normal epithelial cells. Hypoxia as well as knockdown of RECK by siRNA increased the cell cycle progression, the levels of cyclin D1 and c-Myc, and the phosphorylation of Rb protein (p-pRb), but decreased the expression of p21^cip1, p27^kip1, and p16^ink4A. HIF-2α was upregulated by knockdown of RECK, indicating HIF-2α is a downstream target of RECK. As knockdown of RECK induced the activation of epidermal growth factor receptor (EGFR) and treatment of an EGFR kinase inhibitor, gefitinib, suppressed HIF-2α expression induced by the silencing of RECK, we can suggest that the RECK silenicng-EGFR-HIF-2α axis might be a key molecular mechanism to induce hyperplastic phenotype of epithelial cells. It was also found that shRNA of RECK induced larger and more numerous colonies than control cells in an anchorage-independent colony formation assay. Using a xenograft assay, epithelial cells with stably transfected with shRNA of RECK formed a solid mass earlier and larger than those with control cells in nude mice. In conclusion, the suppression of RECK may promote the development of early tumorigenic hyperplastic characteristics in hypoxic stress.

• Animals
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Cell Hypoxia/physiology
• Colony-Forming Units Assay
• ErbB Receptors/metabolism
• GPI-Linked Proteins/genetics
• GPI-Linked Proteins/metabolism
• Gefitinib
• Gene Expression Regulation/drug effects
• Gene Expression Regulation/genetics
• Gene Knockdown Techniques
• Hyperplasia/genetics
• Mice
• Mice, Nude
• Phenotype
• Quinazolines
• RNA, Small Interfering/genetics

Signal transducer and activator of transcription 3 (STAT3) activation is frequently found in human lung cancer and is associated with increased metastasis and reduced survival. How STAT3 enhances invasiveness is unclear.

The expression of microRNAs and target genes was measured by real-time RT–PCR. Protein level was studied by western blotting. Luciferase reporter assay was used to confirm the direct targeting of microRNAs. Gelatin zymography was used to study matrix metalloproteinase (MMP) activity. Transwell assay was used to investigate cell migration and invasion.

Enforced expression of STAT3 decreases the endogenous MMP inhibitor RECK protein but not mRNA level in H460 cells. Conversely, STAT3 inhibitor S3I-201 increases RECK protein in STAT3-activating H1299 cells. We demonstrate that STAT3 upregulates miR-92a to repress RECK via post-transcriptional inhibition. The RECK 3′-untranslated region (3′UTR) reporter activity assay suggests that RECK is a direct repression target of miR-92a. Delivery of pre-miR-92a reduces RECK protein level whereas transfection of anti-miR-92a restores STAT3-induced downregulation of RECK. Anti-miR-92a attenuates MMP activity, migration and invasion of H1299 cells and STAT3-overexpressing H460 cells, suggesting miR-92a is critical for STAT3-induced invasiveness.

The STAT3-induced miR-92a promotes cancer invasion by suppressing RECK and targeting of the STAT3/miR-92a axis may be helpful for cancer treatment.

The oncogene microRNA-21 (miRNA; miR-21) is overexpressed in most solid organ tumours; however, a recent examination of stage II colorectal cancer (CRC) specimens suggests this may be a stromal phenomenon and not only a feature of cancer cells. In vitro and in vivo studies show that miR-21 has potent pro-metastatic effects in various malignant carcinoma cell lines. The tumour microenvironment has also been identified as a key actor during the metastatic cascade; however to date the significance of deregulated miR-21 expression within the cancer-associated stroma has not been examined. In the present study, a quantitative RT-PCR-based analysis of laser microdissected tissue confirmed that miR-21 expression is associated with a four-fold mean increase in CRC stroma compared with normal tissue. In situ hybridisation using locked nucleic acid probes localised miR-21 expression predominantly to fibroblasts within tumour-associated stroma. To study the molecular and biological impact of deregulated stromal miR-21 in CRC, stable ectopic expression was induced in immortalised fibroblasts. This resulted in upregulated α-smooth muscle actin expression implying miR-21 overexpression is driving the fibroblast-to-myofibroblast transdifferentiation. Conditioned medium from miR-21-overexpressing fibroblasts protected CRC cells from oxaliplatin-induced apoptosis and increased their proliferative capacity. 3D organotypic co-cultures containing fibroblasts and CRC cells revealed that ectopic stromal miR-21 expression was associated with increased epithelial invasiveness. Reversion-inducing cysteine-rich protein with kazal motifs, an inhibitor of matrix-remodelling enzyme MMP2, was significantly downregulated by ectopic miR-21 in established and primary colorectal fibroblasts with a reciprocal rise in MMP2 activity. Inhibition of MMP2 abrogated the invasion-promoting effects of ectopic miR-21. This data, which characterises a novel pro-metastatic mechanism mediated by miR-21 in the CRC stroma, highlights the importance of miRNA deregulation within the tumour microenvironment and identifies a potential application for stromal miRNAs as biomarkers in cancer.

The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene was originally identified as a transformation suppressor gene that is widely expressed in normal tissues. In tumor tissues, RECK expression levels are significantly reduced, and the downregulation of RECK has been implicated in tumors that are more aggressive with a poor prognosis. In the present study, RECK expression in peripheral T-cell lymphoma (PTCL; n=82) was examined using immunohistochemistry, and its correlation with clinicopathological factors was analyzed. According to the proportion of positively-stained cells and the staining intensity (SI), the patients were categorized into RECK-negative or RECK-positive groups. RECK expression was observed in 30 of the 82 patients (36.6%). The 3-year survival rate of the patients with RECK-positive tumors (65.5%) was significantly high compared with that of the patients with RECK-negative tumors (20.3%; P=0.046). Reduced RECK expression was found to be significantly correlated with extranodal lymphomatous involvement (P=0.012). The survival analysis showed that RECK-negative expression was an independent and significant factor for predicting a poor prognosis. RECK status is a useful prognostic factor for assessing the biological behavior in PTCL.

• peripheral T-cell lymphoma
• prognosis
• reversion-inducing cysteine-rich protein with Kazal motifs

• 3' Untranslated Regions/genetics
• Blotting, Western
• Cell Line, Tumor
• Cell Movement/genetics
• GPI-Linked Proteins/genetics
• GPI-Linked Proteins/metabolism
• Gene Expression Regulation, Neoplastic
• Green Fluorescent Proteins/genetics
• Green Fluorescent Proteins/metabolism
• HEK293 Cells
• HeLa Cells
• Humans
• Matrix Metalloproteinase 9/genetics
• Matrix Metalloproteinase 9/metabolism
• MicroRNAs/genetics
• Models, Genetic
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Staging
• Neuroblastoma/genetics
• Neuroblastoma/metabolism
• Neuroblastoma/pathology
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Spectrometry, Fluorescence

• matrix metalloproteinase
• tissue inhibitor of matrix metalloproteinase
• colorectal cancer
• adenoma
• tumor progression
• invasion
• metastasis
• prognosis
• biomarker

• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/blood
• Biomarkers, Tumor/metabolism
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Extracellular Matrix/metabolism
• Humans
• Matrix Metalloproteinases/blood
• Matrix Metalloproteinases/genetics
• Matrix Metalloproteinases/metabolism
• Polymorphism, Single Nucleotide
• Tissue Inhibitor of Metalloproteinases/blood
• Tissue Inhibitor of Metalloproteinases/genetics
• Tissue Inhibitor of Metalloproteinases/metabolism

• Animals
• Cells, Cultured
• Epithelial Cells/drug effects
• Epithelial Cells/metabolism
• Estradiol/analogs & derivatives
• Estradiol/pharmacology
• Estrogen Antagonists/pharmacology
• Female
• Fulvestrant
• GPI-Linked Proteins/antagonists & inhibitors
• GPI-Linked Proteins/genetics
• GPI-Linked Proteins/metabolism
• Gene Expression Regulation/drug effects
• Gene Expression Regulation, Enzymologic/drug effects
• Humans
• Matrix Metalloproteinase 2/genetics
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/genetics
• Matrix Metalloproteinase 9/metabolism
• Matrix Metalloproteinase Inhibitors/metabolism
• Matrix Metalloproteinase Inhibitors/pharmacology
• Mice
• RNA, Small Interfering/pharmacology
• Stromal Cells/drug effects
• Stromal Cells/metabolism
• Uterus/drug effects
• Uterus/enzymology
• Uterus/metabolism

Extracellular matrix homeostasis is strictly maintained by a coordinated balance between the expression of metalloproteinases (MMPs) and their inhibitors. The purpose of this study was to investigate whether the expression of MMP-9, MMP-2 and its specific inhibitors, are expressed in a reproducible, specific pattern and if the profiles are related to prognosis in Bladder Cancer (BC).

MMP-9, MMP-2 and its specific inhibitors expression levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in fresh-frozen malignant tissue collected from 40 patients with BC submitted to transurethral resection of bladder. The control group consisted of normal bladder tissue from five patients who had undergone retropubic prostatectomy to treat benign prostatic hyperplasia.

MMP-9 was overexpressed in 59.0 % of patients, and MMP-2, TIMP-1, TIMP-2, MMP-14, RECK and IL-8 was underexpressed in most of the patients. Regarding prognostic parameters we observed that high-grade tumors exhibited significantly higher levels of MMP-9 and IL-8 (p = 0.012, p = 0.003). Invasive tumors (pT1-pT2) had higher expression levels of MMP-9 than superficial tumors (pTa) (p = 0.026). The same was noted for IL-8 that was more expressed by invasive tumors (p = 0.015, p = 0.048). Most importantly tumor recurrence was related with higher levels of both MMP-9 (p = 0.003) and IL-8 (p = 0.005).

We have demonstrated that the overexpression of MMP-9 and higher expression of IL-8 are related to unfavorable prognostic factors of urothelial bladder cancer and tumor recurrence and may be useful in the follow up of the patients.

Cervical cancer is the third most common cancer in women worldwide. Persistent infection with high-risk HPV types, principally HPV16 and 18 is the main risk factor for the development of this malignancy. However, the onset of invasive tumor occurs many years after initial exposure in a minority of infected women. This suggests that other factors beyond viral infection are necessary for tumor establishment and progression. Tumor progression is characterized by an increase in secretion and activation of matrix metalloproteinases (MMPs) produced by either the tumor cells themselves or tumor-associated fibroblasts or macrophages. Increased MMPs expression, including MMP-2, MMP-9 and MT1-MMP, has been observed during cervical carcinoma progression. These proteins have been associated with degradation of ECM components, tumor invasion, metastasis and recurrence. However, few studies have evaluated the interplay between HPV infection and the expression and activity of MMPs and their regulators in cervical cancer. We analyzed the effect of HPV16 oncoproteins on the expression and activity of MMP-2, MMP-9, MT1-MMP, and their inhibitors TIMP-2 and RECK in cultures of human keratinocytes. We observed that E7 expression is associated with increased pro-MMP-9 activity in the epithelial component of organotypic cultures, while E6 and E7 oncoproteins co-expression down-regulates RECK and TIMP-2 levels in organotypic and monolayers cultures. Finally, a study conducted in human cervical tissues showed a decrease in RECK expression levels in precancer and cancer lesions. Our results indicate that HPV oncoproteins promote MMPs/RECK-TIMP-2 imbalance which may be involved in HPV-associated lesions outcome.

• Base Sequence
• Cell Line
• DNA Primers/genetics
• Down-Regulation
• Female
• GPI-Linked Proteins/genetics
• GPI-Linked Proteins/metabolism
• Host-Pathogen Interactions
• Human papillomavirus 16/genetics
• Human papillomavirus 16/pathogenicity
• Human papillomavirus 16/physiology
• Humans
• Keratinocytes/metabolism
• Keratinocytes/virology
• Matrix Metalloproteinase 14/metabolism
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase 9/metabolism
• Matrix Metalloproteinases/metabolism
• Oncogene Proteins, Viral/genetics
• Oncogene Proteins, Viral/physiology
• Papillomavirus E7 Proteins/genetics
• Papillomavirus E7 Proteins/physiology
• Papillomavirus Infections/etiology
• Papillomavirus Infections/genetics
• Papillomavirus Infections/metabolism
• Papillomavirus Infections/virology
• Tissue Inhibitor of Metalloproteinase-2/metabolism
• Uterine Cervical Neoplasms/etiology
• Uterine Cervical Neoplasms/genetics
• Uterine Cervical Neoplasms/metabolism
• Uterine Cervical Neoplasms/virology
• Uterine Cervical Dysplasia/etiology
• Uterine Cervical Dysplasia/genetics
• Uterine Cervical Dysplasia/metabolism
• Uterine Cervical Dysplasia/virology

• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/genetics
• Case-Control Studies
• DNA Primers/genetics
• GPI-Linked Proteins/genetics
• Genetic Association Studies
• Genetic Predisposition to Disease/genetics
• Humans
• Liver Neoplasms/epidemiology
• Liver Neoplasms/genetics
• Logistic Models
• Neoplasm Metastasis/genetics
• Polymorphism, Restriction Fragment Length/genetics
• Polymorphism, Single Nucleotide/genetics
• Real-Time Polymerase Chain Reaction
• Risk Factors
• Statistics, Nonparametric
• Taiwan/epidemiology