4314

MMP3

matrix metallopeptidase 3;MMP3;matrix metallopeptidase 3

matrix metallopeptidase 3 (stromelysin 1, progelatinase)|matrix metalloproteinase 3 (stromelysin 1, progelatinase)|matrix metalloproteinase-3|proteoglycanase|stromelysin-1|transin-1

11q22.3

protein-coding

In order to study the expression of MMP2, MMP3 and MMP9 in breast cancer brain metastasis, we used a syngeneic rat model of distant metastasis of ENU1564, a carcinogen-induced mammary adenocarcinoma cell line. At six weeks post inoculation we observed development of micro-metastasis in the brain. Immunohistochemistry and Western Blotting analyses showed that MMP-2, -3 and -9 proteins expressions are consistently significantly higher in neoplastic brain tissue compared to normal brain tissue. These results were confirmed by RT-PCR. In situ zymography revealed gelatinase activity within the brain metastasis. Gel zymography showed increase in MMP2 and MMP3 activity in brain metastasis. Furthermore, we were able to significantly decrease the development of breast cancer brain metastasis in animals by treatment with PD 166793, a selective synthetic MMP inhibitor. In addition, PD 166793 decreased the in vitro invasive cell behavior of ENU1546. Together our results suggest that MMP-2, -3 and -9 may be involved in the process of metastasis of breast cancer to the brain.

Utilising archival human breast cancer biopsy material we examined the stromal/epithelial interactions of several matrix metalloproteinases (MMPs) using in situ-RT-PCR (IS-RT-PCR). In breast cancer, the stromal/epithelial interactions that occur, and the site of production of these proteases, are central to understanding their role in invasive and metastatic processes. We examined MT1-MMP (MMP-14, membrane type-1-MMP), MMP-1 (interstitial collagenase) and MMP-3 (stromelysin-1) for their localisation profile in progressive breast cancer biopsy material (poorly differentiated invasive breast carcinoma (PDIBC), invasive breast carcinomas (IBC) and lymph node metastases (LNM)). expression of MT1-MMP, MMP-1 and MMP-3 was observed in both the tumour epithelial and surrounding stromal cells in most tissue sections examined. MT1-MMP expression was predominantly localised to the tumour component in the pre-invasive lesions. MMP-1 gene expression was relatively well distributed between both tissue compartments, while MMP-3 demonstrated highest expression levels in the stromal tissue surrounding the epithelial tumour cells. The results demonstrate the ability to distinguish compartmental gene expression profiles using IS-RT-PCR. Further, we suggest a role for MT1-MMP in early tumour progression, expression of MMP-1 during metastasis and focal expression pattern of MMP-3 in areas of expansion. These expression profiles may provide markers for early breast cancer diagnoses and present potential therapeutic targets.

The matrix metalloproteinases (MMPs), a family of proteolytic enzymes that degrade different components of the extracellular matrix, play important roles in tumor development and invasion. A single adenine insertion/deletion polymorphism (6A/5A) in the MMP3 promoter region causes transcriptional elevation. The aim of this study was to assess the effects of this single nucleotide polymorphism (SNP) on the development and clinical staging of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA). The MMP3 SNP was genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis in 417 cancer patients (234 ESCC and 183 GCA) and 350 controls in north China. The overall distribution of the MMP3 SNP in ESCC and GCA patients was not significantly different from that in healthy controls. However, smoking individuals with the 5A/5A or 5A/6A genotype were significantly more common in ESCC patients than in controls (37.5 versus 23.3%, xi(2) = 5.13, P = 0.02). Thus, smokers with at least one 5A allele had a significantly increased risk of ESCC, compared with 6A homozygotes (age and sex adjusted OR = 1.95, 95% CI = 1.08-3.53). The significant difference in the SNP distribution between ESCC patients, GCA patients and controls was not observed when stratified by family history of upper gastrointestinal cancer. In addition, the frequency of the 5A/5A + 5A/6A genotypes in ESCC patients with and without lymphatic metastasis was significantly different (45.8 versus 27.8%, xi(2) = 4.56, P = 0.03). Therefore, patients with at least one 5A allele were significantly more prone to lymphatic metastasis of ESCC. In contrast, no significant difference in the SNP distribution between patients with and without lymphatic metastasis was observed in GCA. The present study suggests that the MMP3 promoter SNP might be associated with a risk of development and lymphatic metastasis in ESCC but not in GCA.

Phosphoglucose isomerase/autocrine motility factor (PGI/AMF) catalyzes the isomerization between glucose-6-phosphate and fructose-6-phosphate, and is involved in cytokine activity, mitogenesis, differentiation, oncogenesis, and tumor metastasis. Presently, we demonstrate that exogenous PGI/AMF stimulates the migration of Huh7 and HepG2 hepatoma cells, but not Hep3B cells. Inhibition of PGI/AMF by PGI/AMF specific inhibitor 5-phospho-D-arabinonate markedly repressed the cellular migration. RT-PCR was used to examine the expression profile of matrix metalloproteinases (MMPs). MMP-3 transcripts, protein level, and secreted form were significantly upregulated in PGI/AMF-treated Huh7 and HepG2 cells, but not in Hep3B cells. MMP-3 inhibition abolished the PGI/AMF-induced cell motility. The observations are consistent with a downstream mediation role of MMP-3 in PGI/AMF-stimulated tumor cell metastasis.

Cyclophilin A (CypA) is a member of peptidyl prolyl isomerases (PPIases), which catalyze the cis/trans isomerization of prolyl peptide bonds on the NH-terminal side of Pro residues in peptide chains. Altered expression of CypA has been reported in hepatocellular carcinoma (HCC), but the biological functions of CypA in HCC remain unknown. We found that the level of CypA expression correlated with the metastatic capability of two HCC cell lines, MHCC97-L and MHCC97-H. Stable expression of ectopic CypA in SK-Hep1 cells promotes cell adhesion, motility, chemotaxis, and in vivo lung metastasis, without affecting cell proliferation. We further analyzed microarray results to identify target genes controlled by CypA. Twenty-one genes related to metastasis were altered by CypA over-expression. A member of matrix metalloproteinase, MMP3, was identified by microarray analysis. The regulation of MMP3 and its homologue MMP9 by CypA were further confirmed by quantitative real-time RT-PCR and zymography assay. Taken together, our data suggest that CypA promotes HCC cell metastasis at least partially through up-regulation of MMP3 and MMP9.

OBJECTIVE: To test the expression of NF-kappaB/p65, MMP-3 and MMP-9 in nasopharyngeal carcinoma (NPC), and analyze their relationship and the clinical significance. METHOD: All samples were examined for the expression of NF-kappaB/p65, MMP-3 and MMP-9 by streptavidin-peroxidase immunohistochemistry. Chi2-test and Spearman-test were used to exam the correlation within them and the expression difference between nasopharyngeal carcinoma and normal nasopharyngeal mucosa. RESULT: Positive expression rate of NF-kappaB/p65 in nasopharyngeal carcinoma was 78.0%; positive expressions rate of MMP-3 and MMP-9 in nasopharyngeal carcinoma were 75.6%. There was positive relationship between NF-kappaB/p65, MMP-3, MMP-9 and N stage. The expression of NF-kappaB/p65 showed a significant positive correlation with the expression of MMP-3 and MMP-9. MMP-3 also had a significant positive correlation with MMP-9. CONCLUSION: The result suggests that NF-kappaB/p65, MMP-3 and MMP-9 are highly expressed in nasopharyngeal carcinoma cells. Their expression is correlated with lymph nodes metastasis, but do not have relationship with sex, age, pathological classification and clinical stage. Each of them has positive correlation with the others.

Matrix metalloproteinases (MMPs) are elevated in patients with squamous cell carcinoma (SCC) over either the head and neck (HNSCC) or the esophagus (ESCC). Synchronous SCC with both HNSCC and ESCC predispose to worse survival. This study tested if serum MMP levels correlate with clinical features and predict survival for HNSCC, ESCC, and synchronous SCC. One hundred and thirty patients with SCCs in upper aero-digestive tract (70 ESCC, 20 HNSCC, and 40 synchronous SCC) and 74 healthy controls were assessed for serum MMP-3, -7, and -9 titers by enzyme-linked immunosorbent assay. The titers were validated to their correlations to clinical features and survival rates of the different SCC groups. Patients with SCCs had significantly higher serum MMP-3, -7, and -9 titers than the controls (P < 0.001) but there was no difference among the three SCC groups. Based on the optimal MMP cut-off values by ROC curve, elevated MMP-3 and MMP-9, but not MMP-7, correlated with distant metastasis and poor survival (P < 0.05). Concomitantly elevated MMP-3 (>14 ng/mL) and MMP-9 (>329.3 ng/mL) independently correlated with poor two-year survival (P = 0.002, by log rank test). Cox regression confirmed that such concomitant elevation was superior to the tumor stage of either ESCC or HNSCC in predicting survival for synchronous SCC. Serum MMPs are elevated in SCC of the upper aero-digestive tract. Especially for synchronous SCC, concomitantly elevated MMP-3 and MMP-9 levels serve as better biomarkers to predict prognosis than TNM staging of ESCC or HNSCC.