MMP11

Gene Summary

Gene:MMP11; matrix metallopeptidase 11
Aliases: ST3, SL-3, STMY3
Location:22q11.23
Summary:Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. However, the enzyme encoded by this gene is activated intracellularly by furin within the constitutive secretory pathway. Also in contrast to other MMP's, this enzyme cleaves alpha 1-proteinase inhibitor but weakly degrades structural proteins of the extracellular matrix. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:stromelysin-3
HPRD
Source:NCBIAccessed: 16 March, 2015

Ontology:

What does this gene/protein do?
Show (12)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 16 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Sp1 Transcription Factor
  • Nucleic Acid Hybridization
  • Xenopus laevis
  • Tetradecanoylphorbol Acetate
  • Chromosome 22
  • Gene Expression
  • Urokinase-Type Plasminogen Activator
  • Lung Cancer
  • Carcinoma
  • MMP11
  • Neoplasm Proteins
  • Squamous Cell Carcinoma
  • Estrogen Receptors
  • Cancer Gene Expression Regulation
  • RNA, Ribosomal, 28S
  • Wound Healing
  • Uterine Cancer
  • Young Adult
  • Breast Cancer
  • Adenocarcinoma
  • RNA
  • Metalloendopeptidases
  • Enzymologic Gene Expression Regulation
  • Fibroblasts
  • Lymphatic Metastasis
  • Neoplasm Invasiveness
  • Gene Expression Profiling
  • Northern Blotting
  • In Situ Hybridization
  • Transcription
  • Cancer RNA
  • Esophageal Cancer
  • Stromal Cells
  • Cell Movement
  • Messenger RNA
  • Skin Cancer
  • Disease Progression
  • Oligonucleotide Array Sequence Analysis
  • Receptors, Urokinase Plasminogen Activator
  • Neoplasm Metastasis
  • Immunohistochemistry
  • Tumor Markers
Tag cloud generated 16 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerMMP11 Expression in Breast CancerPrognostic
MMP11 (stromelysin 3) expression has been linked to prognosis in breast cancer. For example Ahmad et al (1998) found that MMP11 expression significant prognostic factor for disease-free survival in multivariate analysis of patients with node-positive invasive ductal carcinomas. Tetu et al (1998) found that 87% of 665 breast cancer cases (both node +ve and node -ve) expressed MMP11. High levels of MMP11 were associated with expression and a younger age, lymph node involvement, poor nuclear grade, ductal histology, aneuploidy, and HSP-27 expression. In this study MMP11 expression was a statistically significant prognostic factor in univariate analysis, but not in multivariate analysis.
View Publications25
Lung CancerMMP11 and Lung Cancer View Publications9
Esophageal CancerMMP11 and Esophageal Cancer View Publications5
Uterine SarcomaMMP11 and Uterine Cancer View Publications4
Skin CancerMMP11 and Skin Cancer View Publications2

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MMP11 (cancer-related)

Wu D, Li M, Wang L, et al.
microRNA‑145 inhibits cell proliferation, migration and invasion by targeting matrix metallopeptidase-11 in renal cell carcinoma.
Mol Med Rep. 2014; 10(1):393-8 [PubMed] Related Publications
microRNA‑145 (miR‑145) has been reported to be frequently downregulated in various types of cancer, including renal, prostate, bladder, lung and colon cancer, as well as B‑cell malignancies. The present study examined the effects of miR‑145 on the cell proliferation, migration and invasion of renal cell carcinoma (RCC). Following transfection of miR‑145, an MTT, cell migration, cell invasion and luciferase assays, and western blot analysis were conducted in RCC cell lines. The present study demonstrated that miR‑145 inhibited cell proliferation, migration and invasion in 786‑O and A498 cells. The present study also demonstrated for the first time, to the best of our knowledge, that miR‑145 may directly target matrix metallopeptidase‑11 (MMP‑11) in RCC. miR‑145 was demonstrated to suppress cell proliferation, migration and invasion by targeting MMP‑11 in RCC cell lines. These results suggested that it may be investigated as a predictive marker for the early detection of tumor metastasis and for targeting therapeutic drugs to inhibit the invasion of RCC.

Kou YB, Zhang SY, Zhao BL, et al.
Knockdown of MMP11 inhibits proliferation and invasion of gastric cancer cells.
Int J Immunopathol Pharmacol. 2013 Apr-Jun; 26(2):361-70 [PubMed] Related Publications
Matrix metalloproteinase 11 (MMP11 or stromelysin-3) has recently been reported to play a crucial role in the development and progression of multiple malignancies. The aim of this study was to investigate the function of MMP11 expression in human gastric adenocarcinoma (GAC). Using immunohistochemistry assay, we studied the expression level of MMP11 in GAC and adjacent non-cancerous tissues (ANCT). The association between MMP11 expression and tumor size and pathological grade, as well as metastatic potential was analyzed. Through small hairpin RNA (shRNA)-mediated MMP11 knockdown in SGC-7901 GAC cells, we observed the changes of the biological behaviors of GAC cells. Our results indicated that the rate of positive expression of MMP11 was higher in GAC tissues than in ANCT (55.0 vs 30.0 percent, P=0.025). MMP11 expression had no association with the factors of age or gender of the GAC patients, or the size, pathological staging and lymph node metastases of the tumors (each P greater than 0.05). Furthermore, MMP11 knockdown inhibited the proliferative activities and invasive potential of SGC-7901 GAC cells with decreased expression of IGF-1, PCNA and VEGF. Taken together, our findings demonstrated that MMP11 expression was increased in GAC tissues, but did not correlate with the clinicopathologic features. Knockdown of MMP11 expression could inhibit the proliferation and invasion of GAC cells probably through down-regulation of the IGF-1 signaling pathway, suggesting that MMP11 might be a potential therapeutic target for the treatment of gastric cancer.

Du WW, Fang L, Li M, et al.
MicroRNA miR-24 enhances tumor invasion and metastasis by targeting PTPN9 and PTPRF to promote EGF signaling.
J Cell Sci. 2013; 126(Pt 6):1440-53 [PubMed] Related Publications
MicroRNAs are known to play regulatory roles in gene expression associated with cancer development. We analyzed levels of the microRNA miR-24 in patients with breast carcinoma and found that miR-24 was higher in breast carcinoma samples than in benign breast tissues. We generated constructs expressing miR-24 and studied its functions using both in vitro and in vivo techniques. We found that the ectopic expression of miR-24 promoted breast cancer cell invasion and migration. In vivo experiments in mice indicated that the expression of miR-24 enhanced tumor growth, invasion into local tissues, metastasis to lung tissues and decreased overall mouse survival. In the miR-24-expressing cells and tumors, EGFR was highly phosphorylated, whereas expression of the phosphatases tyrosine-protein phosphatase non-receptor type 9 (PTPN9) and receptor-type tyrosine-protein phosphatase F (PTPRF) were repressed. We confirmed that miR-24 could directly target both PTPN9 and PTPRF. Consistent with this, we found that the levels of phosphorylated epidermal growth factor receptor (pEGFR) were higher whereas the levels of PTPN9 and PTPRF were lower in the patients with metastatic breast carcinoma. Ectopic expression of PTPN9 and PTPRF decreased pEGFR levels, cell invasion, migration and tumor metastasis. Furthermore, we found that MMP2, MMP11, pErk, and ADAM15 were upregulated, whereas TIMP2 was downregulated; all of which supported the roles of miR-24 in tumor invasion and metastasis. Our results suggest that miR-24 plays a key role in breast cancer invasion and metastasis. miR-24 could potentially be a target for cancer intervention.

Sunil Kumar BV, Kumar KA, Padmanath K, et al.
Heterologous expression and functional characterization of matrix metalloproteinase-11 from canine mammary tumor.
Anim Biotechnol. 2013; 24(1):31-43 [PubMed] Related Publications
Matrix metalloproteinases (MMPs) are reported to be involved in tumor growth, apoptosis, angiogenesis, invasion, and development of metastases. These are zinc containing metalloproteases, known for their role in extracellular matrix degradation. MMP-11 (stromelysin3) is reported to be highly expressed in breast cancer, therefore it may act as marker enzyme for breast cancer progression. The present work was carried out to produce recombinant canine (Canis lupus familiaris) MMP-11 lacking the signal and propeptide in E. coli by optimizing its expression and purification in biologically active form and to functionally characterize it. A bacterial protein expression vector pPROEX HTc was used. The MMP-11 mature peptide encoding gene was successfully cloned and expressed in E. coli and the purified recombinant enzyme was found to be functionally active. The recombinant enzyme exhibited caseinolytic activity and could be activated by Trypsin and 4-Amino phenyl mercuric acetate (APMA). However Ethylene diamine tertra acetate (EDTA) inhibited the enzyme's caseinolytic activity. The recombinant enzyme degraded extracellular matrix constituents and facilitated migration of MDCK (Madin-Darby canine kidney) cells through BD Biocoat Matrigel invasion chambers. These results suggest that in vivo MMP-11 could play a significant role in the turnover of extracellular matrix constituents.

Tang S, Gao L, Bi Q, et al.
SDR9C7 promotes lymph node metastases in patients with esophageal squamous cell carcinoma.
PLoS One. 2013; 8(1):e52184 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The major reason for the poor prognosis of esophageal squamous cell carcinoma (ESCC) patients is lymph node (LN) metastases.
METHODOLOGY/PRINCIPAL: In the present study, gene expression profiling assay (GEP) was performed to identify the differences in gene expression profiles between primary ESCC tumors that were with LN metastases (N(+)) and those without LN metastases (N(-)).
CONCLUSIONS/SIGNIFICANCE: A total of 23 genes were identified as being significantly elevated, and 30 genes were sharply decreased in ESCC tumors that were N(+) compared with N- tumors. Among these genes, two transcripts of the short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) were observed 7 times more frequently in N(+) compared with N(-) tumors. Immunohistochemical staining showed that SDR9C7 expression closely correlated with metastasis, and would be a prognostic marker for ESCC patients. To investigate the role of SDR9C7 in the ESCC metastasis, repeated transwell assays were adopted to establish highly and non-invasive ESCC sublines, and western blot showed that SDR9C7 expression was markedly higher in highly invasive cells compared with non-invasive ones. Down-regulation of SDR9C7 dramatically inhibited the metastatic abilities in vitro and in vivo, and repressed the expression of MMP11 in highly invasive cells, indicating that SDR9C7 promotes ESCC metastasis partly through regulation of MMP11, and might be a potential prognostic and therapeutic marker for ESCC patients.

Siragam V, Rutnam ZJ, Yang W, et al.
MicroRNA miR-98 inhibits tumor angiogenesis and invasion by targeting activin receptor-like kinase-4 and matrix metalloproteinase-11.
Oncotarget. 2012; 3(11):1370-85 [PubMed] Free Access to Full Article Related Publications
Angiogenesis and invasion are essential processes for solid tumor growth and dissemination. The tumor development process can be dependent on the activation of a series of signaling pathways, including growth factor-activated pathways. MicroRNAs have been shown to be critical for tumorigenesis, but their roles in cancer angiogenesis, invasion and other signaling pathways important for tumor development are still unclear in the context of tumor biology. We investigated the role of microRNA miR-98 in regulating tumor growth, invasion, and angiogenesis using a highly aggressive breast cancer model in vitro and in vitro. We found that the expression of miR-98 inhibited breast cancer cell proliferation, survival, tumor growth, invasion, and angiogenesis. Conversely, inhibition of endogenous miR-98 promoted cell proliferation, survival, tumor growth, invasion, and angiogenesis. It appeared that miR-98 inhibited angiogenesis by modulating endothelial cell activities including cell spreading, cell invasion and tubule formation. Interestingly, miR-98 reduced the expression of ALK4 and MMP11, both of which were potential targets of miR-98. Transfection of an anti-miR-98 construct increased the expression of both targets. We confirmed that mir-98 targeted the 3'-untranslated regions of ALK4 and MMP11. Finally, ALK4- and MMP11-specific siRNAs inhibited breast cancer cell proliferation, survival, and angiogenesis. Rescue experiments with ALK4 and MMP11 constructs reversed the anti-proliferative, anti-invasive and anti-angiogenic effects of miR-98. Our findings define a regulatory role of miR-98 in tumor angiogenesis and invasion through repressed ALK4 and MMP11 expression.

Shin NR, Jeong EH, Choi CI, et al.
Overexpression of Snail is associated with lymph node metastasis and poor prognosis in patients with gastric cancer.
BMC Cancer. 2012; 12:521 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Epithelial-mesenchymal transition (EMT) plays a significant role in tumor progression and invasion. Snail is a known regulator of EMT in various malignant tumors. This study investigated the role of Snail in gastric cancer.
METHODS: We examined the effects of silenced or overexpressed Snail using lenti-viral constructs in gastric cancer cells. Immunohistochemical analysis of tissue microarrays from 314 patients with gastric adenocarcinoma (GC) was used to determine Snail's clinicopathological and prognostic significance. Differential gene expression in 45 GC specimens with Snail overexpression was investigated using cDNA microarray analysis.
RESULTS: Silencing of Snail by shRNA decreased invasion and migration in GC cell lines. Conversely, Snail overexpression increased invasion and migration of gastric cancer cells, in line with increased VEGF and MMP11. Snail overexpression (≥75% positive nuclear staining) was also significantly associated with tumor progression (P < 0.001), lymph node metastases (P = 0.002), lymphovascular invasion (P = 0.002), and perineural invasion (P = 0.002) in the 314 GC patients, and with shorter survival (P = 0.023). cDNA microarray analysis revealed 213 differentially expressed genes in GC tissues with Snail overexpression, including genes related to metastasis and invasion.
CONCLUSION: Snail significantly affects invasiveness/migratory ability of GCs, and may also be used as a predictive biomarker for prognosis or aggressiveness of GCs.

Eiró N, González L, González LO, et al.
Relationship between the inflammatory molecular profile of breast carcinomas and distant metastasis development.
PLoS One. 2012; 7(11):e49047 [PubMed] Free Access to Full Article Related Publications
Inflammatory conditions may promote tumor progression and aggressiveness. In previous reports, we found a group of breast cancer tumors characterized by metalloprotease-11 (MMP-11) expression by intratumoral mononuclear inflammatory cells (MICs), which was associated with distant metastasis development. Thus, in the present study we evaluated the relationship between MMP-11 expression by MICs, distant metastasis development, and a wide panel of inflammatory factors in breast carcinoma. In an initial approach, we analyzed 65 factors associated with tumor progression and inflammation, in a tumor population classified in good or bad prognosis, based on MMP-11 expression by intratumoral MICs. The most differentially expressed factors were then analyzed in a wider tumor population classified according to MMP-11 expression by MICs and also according to metastasis development. These analyses were carried out by Real-time PCR. The results showed that of the 65 starting factors analyzed, those related with MMP-11 expression by MICs were: IL-1, -5, -6, -8, -17, -18, MMP-1, TIMP-1, ADAM-8, -10, -15, -23, ADAMTS-1, -2, -15, Annexin A2, IFNβ, Claudin-3, CCL-3, MyD88, IRAK-4 and NFκB. Of them, factors more differentially expressed between both groups of tumors were IL-1, IL-5, IL-6, IL-17, IFNβ and NFκB. Thereafter, we confirmed in the wider tumor population, that there is a higher expression of those factors in tumors infiltrated by MMP-11 positive MICs. Altogether these results indicate that tumors developing worse prognosis and identified by MMP-11 expression by intratumoral MICs, shows an up-regulation of inflammatory-related genes.

Mali AV, Wagh UV, Hegde MV, et al.
In vitro anti-metastatic activity of enterolactone, a mammalian lignan derived from flax lignan, and down-regulation of matrix metalloproteinases in MCF-7 and MDA MB 231 cell lines.
Indian J Cancer. 2012 Jan-Mar; 49(1):181-7 [PubMed] Related Publications
BACKGROUND: Actin cytoskeleton is involved in actin-based cell adhesion, cell motility, and matrix metalloproteinases(MMPs) MMP2, MMP9, MMP11 and MMP14 are responsible for cell invasion in breast cancer metastasis. The dietary intake of lignan from flax seed gets converted to enterolactone (EL) and enterodiol in the human system. Here we show that the enterolactone has a very significant anti-metastatic activity as demonstrated by its ability to inhibit adhesion and invasion and migration in MCF-7 and MDA MB231 cell lines.
MATERIALS AND METHODS: Migration inhibition assay, actin-based cell motility assay along with reverse transcriptase polymerase chain reaction (RT-PCR) for MMP2, MMP9, MMP11 and MMP14 genes were performed in MCF-7 and MDA MB 231 cell lines.
RESULTS: Enterolactone seems to inhibit actin-based cell motility as evidenced by confocal imaging and photo documentation of cell migration assay. The results are supported by the observation that the enterolactone in vitro significantly down-regulates the metastasis-related metalloproteinases MMP2, MMP9 and MMP14 gene expressions. No significant alteration in the MMP11 gene expression was found.
CONCLUSIONS: Therefore we suggest that the anti-metastatic activity of EL is attributed to its ability to inhibit cell adhesion, cell invasion and cell motility. EL affects normal filopodia and lamellipodia structures, polymerization of actin filaments at their leading edges and thereby inhibits actin-based cell adhesion and cell motility. The process involves multiple force-generating mechanisms of actin filaments i.e. protrusion, traction, deadhesion and tail-retraction. By down-regulating the metastasis-related MMP2, MMP9 and MMP14 gene expressions, EL may be responsible for cell invasion step of metastasis.

Bi Q, Tang S, Xia L, et al.
Ectopic expression of MiR-125a inhibits the proliferation and metastasis of hepatocellular carcinoma by targeting MMP11 and VEGF.
PLoS One. 2012; 7(6):e40169 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Studies have been shown that miR-125a plays an important role in carcinogenesis, however, the role of miR-125a in hepatocellular carcinoma (HCC) remains elusive.
METHODOLOGY/PRINCIPAL: Real time-PCR (qRT-PCR) was performed to test the significance of miR-125a in HCC. Ectopic expression of miR-125a was used to test the influences of miR-125a on proliferation and metastasis of HCC cells in vitro and in vivo. Predicted target genes of miR-125a were determined by dual-luciferase reporting, qRT-PCR, and western blot (WB) analyses. Then immunohistochemical staining (IHC) was used to detect the expression of target genes, and the correlations and prognostic values of miR-125a and its target genes were also investigated.
CONCLUSIONS/SIGNIFICANCE: Decreased miR-125a was observed in both HCC tissues and cell lines, and associated with patients' aggressive pathologic features. Up-regulating miR-125a significantly inhibited the malignant phenotypes by repressing the expression of matrix metalloproteinase 11 (MMP11) and vascular endothelial growth factor A (VEGF-A) both in vitro and in vivo. Furthermore, miR-125a expression was inversely correlated with both MMP11 and VEGF-A expression in HCC tissues. Inhibiting miR-125a could increase both MMP11 and VEGF-A expression, and RNA interference targeting MMP11 or VEGF-A mRNA could rescue the loss of miR-125a functions. MiR-125a inhibits the proliferation and metastasis of HCC by targeting MMP11 and VEGF-A. Up-regulation of miR-125a might be a promising approach and a prognostic marker for HCC.

Skrzypczak M, Springwald A, Lattrich C, et al.
Expression of cysteine protease cathepsin L is increased in endometrial cancer and correlates with expression of growth regulatory genes.
Cancer Invest. 2012; 30(5):398-403 [PubMed] Related Publications
Proteases contribute to tumor invasion and metastasis by degrading basement membranes and extracellular matrix (ECM). In this study, we compared gene expression levels of two proteases, cysteine protease Cathepsin L2 (CTSL2) and matrix metalloproteinase MMP11, in human endometrium and endometrial cancer. Our data demonstrate CTSL2 transcript levels to be strongly elevated in endometrial cancer, particularly in G3 tumors. Furthermore, we observed a highly significant positive correlation of CTSL2 with expression of growth regulatory genes Ki-67, cyclin B1, MYBL2, p21/WAF, and HER2 receptor tyrosine kinase. Our data suggest that CTSL2 might be involved in progression of endometrial cancer.

Desmedt C, Majjaj S, Kheddoumi N, et al.
Characterization and clinical evaluation of CD10+ stroma cells in the breast cancer microenvironment.
Clin Cancer Res. 2012; 18(4):1004-14 [PubMed] Related Publications
PURPOSE: There is growing evidence that interaction between stromal and tumor cells is pivotal in breast cancer progression and response to therapy. Based on earlier research suggesting that during breast cancer progression, striking changes occur in CD10(+) stromal cells, we aimed to better characterize this cell population and its clinical relevance.
EXPERIMENTAL DESIGN: We developed a CD10(+) stroma gene expression signature (using HG U133 Plus 2.0) on the basis of the comparison of CD10 cells isolated from tumoral (n = 28) and normal (n = 3) breast tissue. We further characterized the CD10(+) cells by coculture experiments of representative breast cancer cell lines with the different CD10(+) stromal cell types (fibroblasts, myoepithelial, and mesenchymal stem cells). We then evaluated its clinical relevance in terms of in situ to invasive progression, invasive breast cancer prognosis, and prediction of efficacy of chemotherapy using publicly available data sets.
RESULTS: This 12-gene CD10(+) stroma signature includes, among others, genes involved in matrix remodeling (MMP11, MMP13, and COL10A1) and genes related to osteoblast differentiation (periostin). The coculture experiments showed that all 3 CD10(+) cell types contribute to the CD10(+) stroma signature, although mesenchymal stem cells have the highest CD10(+) stroma signature score. Of interest, this signature showed an important role in differentiating in situ from invasive breast cancer, in prognosis of the HER2(+) subpopulation of breast cancer only, and potentially in nonresponse to chemotherapy for those patients.
CONCLUSIONS: Our results highlight the importance of CD10(+) cells in breast cancer prognosis and efficacy of chemotherapy, particularly within the HER2(+) breast cancer disease.

Barrasa JI, Olmo N, Santiago-Gómez A, et al.
Histone deacetylase inhibitors upregulate MMP11 gene expression through Sp1/Smad complexes in human colon adenocarcinoma cells.
Biochim Biophys Acta. 2012; 1823(2):570-81 [PubMed] Related Publications
MMP-11 (stromelysin-3) is a matrix metalloproteinase associated with tumor progression and poor prognosis. Its expression was initially described exclusively in stromal cells surrounding tumors, but more recently it has also been detected in macrophages and hepatocarcinoma cells. Here we show MMP-11 expression in human epithelial colon adenocarcinoma cell lines (Caco-2, HT-29 and BCS-TC2). Treatment of BCS-TC2 cells with butyrate and trichostatin A (TSA) (histone deacetylase inhibitors) increases MMP11 promoter activity and protein expression. Using electrophoretic mobility shift assay (EMSA) and supershift assays, we demonstrate for the first time that Sp1 is able to bind to the GC-boxes within the MMP11 proximal promoter region; this binding has been confirmed by chromatin immunoprecipitation. Sp1 is involved in MMP11 basal expression and it is essential for the upregulation of transcription by histone deacetylase inhibitors as deduced from mutant constructs lacking the Sp1 sites and by inhibition of its binding to the promoter with mithramycin. This regulation requires the formation of Sp1/Smad2 heterocomplexes, which is stimulated by an increase in the acetylation status of Smad after butyrate or TSA treatments. We have also found that ERK1/2-mitogen-activated protein kinase (MAPK), but not p38-MAPK or JNK, is involved in the upregulation of MMP11 by HDAC inhibitors.

Valdivia A, Peralta R, Matute-González M, et al.
Co-expression of metalloproteinases 11 and 12 in cervical scrapes cells from cervical precursor lesions.
Int J Clin Exp Pathol. 2011; 4(7):674-82 [PubMed] Free Access to Full Article Related Publications
The metalloproteinases (MMP) 11 and 12 have been shown to be expressed in cervical cancer (CC). In order to extend our previous results, these MMPs were evaluated in cervical precursor lesions. One hundred seventeen cervical scrapes: thirty-six normal, thirty-six low grade squamous lesions (LSIL), thirty-six high grade (HSIL), nine CC; and, also ninety-nine paraffin-embedded cervical lesions: fifteen normal cervices, thirty eight LSIL, sixteen HSIL, and five CC were collected. The samples were analyzed for relative expression by real time RT-PCR or immunohistochemistry assay. We were able to identify a relative increased expression of MMP11 in 75% and 78% from LSIL and HSIL samples, respectively. While MMP12 expression was 64% and 75% in LSIL and HSIL, respectively. Positive samples for MMP11 expression were also positive for MMP12 expression and also increased according to illness progression. In the tissues, MMP11 or MMP12 expression was observed in the cytoplasm of the neoplastic cells, while in the normal epithelium was absent. The reaction was always stronger for MMP12 than MMP11. MMP11 expression was present in 77% and 66% of LSIL and HSIL, while MMP12 expression was 73% and 68%. There was a relationship between MMP11 or MMP12 expression and HPV infection. Our data are showing a relationship between diagnostic of precursor lesions and the MMP11 and 12 expressions, suggesting that their expression could be an early event in the neoplastic lesions of the cervix and could have clinical significance.

Wang HY, Sun BY, Zhu ZH, et al.
Eight-signature classifier for prediction of nasopharyngeal [corrected] carcinoma survival.
J Clin Oncol. 2011; 29(34):4516-25 [PubMed] Related Publications
PURPOSE: Currently, nasopharyngeal carcinoma (NPC) prognosis evaluation is based primarily on the TNM staging system. This study aims to identify prognostic markers for NPC.
PATIENTS AND METHODS: We detected expression of 18 biomarkers by immunohistochemistry in NPC tumors from 209 patients and evaluated the association between gene expression level and disease-specific survival (DSS). We used support vector machine (SVM)--based methods to develop a prognostic classifier for NPC (NPC-SVM classifier). Further validation of the NPC-SVM classifier was performed in an independent cohort of 1,059 patients.
RESULTS: The NPC-SVM classifier integrated patient sex and the protein expression level of seven genes, including Epstein-Barr virus latency membrane protein 1, CD147, caveolin-1, phospho-P70S6 kinase, matrix metalloproteinase 11, survivin, and secreted protein acidic and rich in cysteine. The NPC-SVM classifier distinguished patients with NPC into low- and high-risk groups with significant differences in 5-year DSS in the evaluated patients (87% v 37.7%; P < .001) in the validation cohort. In multivariate analysis adjusted for age, TNM stage, and histologic subtype, the NPC-SVM classifier was an independent predictor of 5-year DSS in the evaluated patients (hazard ratio, 4.9; 95% CI, 3.0 to 7.9) in the validation cohort.
CONCLUSION: As a powerful predictor of 5-year DSS among patients with NPC, the newly developed NPC-SVM classifier based on tumor-associated biomarkers will facilitate patient counseling and individualize management of patients with NPC.

Han HB, Gu J, Zuo HJ, et al.
Let-7c functions as a metastasis suppressor by targeting MMP11 and PBX3 in colorectal cancer.
J Pathol. 2012; 226(3):544-55 [PubMed] Related Publications
Accumulating evidence shows that microRNAs, functioning as either oncogenes or tumour suppressors by negatively regulating downstream target genes that are actively involved in tumour initiation and progression, may be promising biomarkers and therapy targets. Data mining through a microRNA chip database indicated that let-7c may be associated with tumour metastasis. Here, we confirmed that down-regulation of let-7c in primary cancer tissues was significantly associated with metastases, advanced TNM stages and poor survival of colorectal cancer patients. Moreover, ectopic expression of let-7c in a highly metastatic Lovo cell line remarkably suppressed cell migration and invasion in vitro by the down-regulation of K-RAS, MMP11 and PBX3, as well as tumour growth and metastases in vivo, whereas inhibition of let-7c in low-metastatic HT29 cells increased cell motility and invasion by the enhanced gene expression of K-RAS, MMP11 and PBX3. Interestingly, the luciferase reporters' activities with the 3'-UTRs of K-RAS, MMP11 and PBX3 were inhibited significantly by let-7c. Importantly, rescue experiments involving the over-expression of these genes without their 3'-UTRs completely reversed the effects of let-7c on tumour metastasis, both in vitro and in vivo. Finally, the levels of let-7c were inversely correlated with those of MMP11 and PBX3, but not with those of K-RAS. Taken together, these results demonstrate that let-7c, apart from its tumour growth suppression role, also functions as a tumour metastasis suppressor in colorectal cancer by directly destabilizing the mRNAs of MMP11 and PBX3 at least.

Resende C, Thiel A, Machado JC, Ristimäki A
Gastric cancer: basic aspects.
Helicobacter. 2011; 16 Suppl 1:38-44 [PubMed] Related Publications
Gastric cancer (GC) is a world health burden, ranging as the second cause of cancer death worldwide. Etiologically, GC arises not only from the combined effects of environmental factors and susceptible genetic variants but also from the accumulation of genetic and epigenetic alterations. In the last years, molecular oncobiology studies brought to light a number of genes that are implicated in gastric carcinogenesis. This review is intended to focus on the recently described basic aspects that play key roles in the process of gastric carcinogenesis. Genetic variants of the genes IL-10, IL-17, MUC1, MUC6, DNMT3B, SMAD4, and SERPINE1 have been reported to modify the risk of developing GC. Several genes have been newly associated with gastric carcinogenesis, both through oncogenic activation (GSK3β, CD133, DSC2, P-Cadherin, CDH17, CD168, CD44, metalloproteinases MMP7 and MMP11, and a subset of miRNAs) and through tumor suppressor gene inactivation mechanisms (TFF1, PDX1, BCL2L10, XRCC, psiTPTE-HERV, HAI-2, GRIK2, and RUNX3). It also addressed the role of the inflammatory mediator cyclooxygenase-2 (COX-2) in the process of gastric carcinogenesis and its importance as a potential molecular target for therapy.

Tan EH, Goh C, Lim WT, et al.
Gefitinib, cisplatin, and concurrent radiotherapy for locally advanced head and neck cancer: EGFR FISH, protein expression, and mutational status are not predictive biomarkers.
Ann Oncol. 2012; 23(4):1010-6 [PubMed] Related Publications
BACKGROUND: Gefitinib was demonstrated to be synergistic with cisplatin and radiotherapy (RT) in in vitro studies. Biomarkers predictive of response to gefitinib in squamous cell head and neck cancer is still lacking.
METHODS: Thirty-one patients with locally advanced and easily accessible primary tumor sites for biopsies were recruited. Gefitinib was started 3 weeks before the start of cisplatin/concurrent radiotherapy (CTRT) and continued during the CTRT phase and thereafter for 4 months as consolidation phase. Two baselines and a repeat tumor sample were taken after 2 weeks of gefitinib alone to study its impact on tumor gene expression. Epidermal growth factor receptor (EGFR) protein expression, FISH and mutational status, and matrix metallopeptidase 11 (MMP11) protein expression were correlated with response and survival outcome.
RESULTS: The overall response rate to gefitinib alone was 9.7%. The survival outcome is as follows: median disease free 1.3 years, median survival time 2.4 years, 3-year disease free 42.9%, and 3-year overall survival 48.4%. EGFR FISH, protein expression, and mutational status did not predict for response nor survival outcome of patients. Although MMP11 overexpression did not predict for response, it predicted significantly for a poorer survival outcome.
CONCLUSIONS: Gefitinib can be combined safely with cisplatin/RT. More studies are needed to uncover predictive biomarkers of benefit to gefitinib.

Bukurova IuA, Nikitina SL, Khankin SL, et al.
[Identification of protein markers for serum diagnosis of cancer based on microRNA expression profiling].
Mol Biol (Mosk). 2011 Mar-Apr; 45(2):376-81 [PubMed] Related Publications
A new algorithm has been developed for bioinformatics search of putative serum markers of cancer, which includes: 1) identification of microRNAs that are most often and most significantly overexpressed in tumors; 2) selection of mRNA targets regulated by microRNAs; 3) identification of mRNA targets encoding secreted proteins; 4) comparative analysis of mRNA transcription levels in normal and tumor tissues. Application of the algorithm led to discovery of seven putative serum markers of colon cancer: ADAMTS14, ANGPT2, CCL7, DEFA5, MMP11, MMP14, and PLAU. Experiments demonstrated that production of two out of seven proteins (MMP14 and DEFA5) is significantly increased in colon tumors vs. normal samples.

Delassus GS, Cho H, Eliceiri GL
New signaling pathways from cancer progression modulators to mRNA expression of matrix metalloproteinases in breast cancer cells.
J Cell Physiol. 2011; 226(12):3378-84 [PubMed] Related Publications
We observed previously that each of seven cancer progression inhibitors suppresses the mRNA expression of some matrix metalloproteinases (MMPs), but stimulates that of others, in breast cancer cells. In the present study we tested the effect of overexpressing other cancer modulators on MMP expression. The MMPs tested are MMP1, MMP2, MMP7, MMP13, MMP14, MMP16, MMP19, and MMP25. The proteins that were overexpressed are cancer inhibitors (NME, DRG1, IL10), enhancers (SOD2, FAK, IL17, and CREB), and proteins that suppress cancer progression in cells of some cancers and promote it in others (FUT1, integrin beta3, serpin E1, TIAM1, and claudin 4). Unexpectedly, all of them only lowered MMP mRNA expression, mainly of MMP16, MMP2, and MMP13, in breast cancer cells. Signaling from SOD2 uncoupled the accumulation of two MMP16 mRNA splice variants, suggesting signaling to a late step in MMP16 mRNA accumulation, such as MMP16 mRNA stabilization or late mRNA processing. Signaling that modulates MMP expression differed widely among the total population of MDA-MB-231 cells and single-cell progenies cloned from that population. It also differed substantially between cells of two metastatic breast basal adenocarcinomas, MDA-MB-231 and MDA-MB-468. The present study detected 37 new signaling pathways from cancer progression modulators located upstream of MMP mRNA expression in human breast cancer cells. Our siRNA-induced MMP knockdown data support the interpretation that signaling from MMP19, MMP1, MMP7, MMP12, MMP14, and MMP11 each stimulates the mRNA expression of other MMPs in breast cancer cells.

Pettersen JS, Fuentes-Duculan J, Suárez-Fariñas M, et al.
Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated.
J Invest Dermatol. 2011; 131(6):1322-30 [PubMed] Free Access to Full Article Related Publications
Tumor-associated macrophages (TAMs) may have an important role in tumor immunity. We studied the activation state of TAMs in cutaneous SCC, the second most common human cancer. CD163 was identified as a more abundant, sensitive, and accurate marker of TAMs when compared with CD68. CD163(+) TAMs produced protumoral factors, matrix metalloproteinases 9 and 11 (MMP9 and MMP11), at the gene and protein levels. Gene set enrichment analysis (GSEA) was used to evaluate M1 and M2 macrophage gene sets in the SCC genes and to identify candidate genes in order to phenotypically characterize TAMs. There was coexpression of CD163 and alternatively activated "M2" markers, CD209 and CCL18 (chemokine (C-C motif) ligand 18). There was enrichment for classically activated "M1" genes in SCC, which was confirmed in situ by colocalization of CD163 and phosphorylated STAT1 (signal transducer and activator of transcription 1), IL-23p19, IL-12/IL-23p40, and CD127. Also, a subset of TAMs in SCC was bi-activated as CD163(+) cells expressed markers for both M1 and M2, shown by triple-label immunofluorescence. These data support heterogeneous activation states of TAMs in SCC, and suggest that a dynamic model of macrophage activation would be more useful to characterize TAMs.

Riehle U, Mader A, Brandstetter T, et al.
Nucleic acid sequence-based amplification in formalin-fixed and paraffin-embedded breast-cancer tissues.
J Clin Pathol. 2010; 63(12):1071-6 [PubMed] Related Publications
AIM: To evaluate the nucleic acid sequence-based amplification (NASBA) technique to amplify mRNA isolated from formalin-fixed and paraffin-embedded (FFPE) breast-cancer tissues.
METHODS: RNA was extracted from archived, 10-year-old FFPE tissues, and selected genes, namely ribosomal protein S18 (RPS18), epidermal growth factor receptor 2 (HER2), estrogen receptor alpha (ERα), Y box binding protein (YBX-1), matrix metallopeptidase 11 (MMP11), caspase 8 (CASP8) and superoxide dismutase 2 (SOD2), were amplified by NASBA.
RESULTS: Despite strong degradation of the template, RNA amplification of all tested genes resulted in strong hybridisation signals. Sensitivity tests showed that the RPS18 NASBA assay was more sensitive than real-time RT-PCR used as a reference method. The sensitivity of the HER2, ERα, MMP11, YBX1, CASP8 and SOD2 NASBA assay was comparable with RT-PCR targeted to the respective genes.
CONCLUSIONS: The results obtained indicate that NASBA is suitable to amplify with high specificity and sensitivity, even strongly degraded RNA isolated from FFPE tissues, and therefore can complement already-existing amplification techniques such as RT-PCR for analysis of such tissues.

Wang L, Xiang YN, Zhang YH, et al.
Collagen triple helix repeat containing-1 in the differential diagnosis of dermatofibrosarcoma protuberans and dermatofibroma.
Br J Dermatol. 2011; 164(1):135-40 [PubMed] Related Publications
BACKGROUND: The distinction between dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) is a well-known challenge for dermatopathologists. Immunohistochemical stains have been used to augment routine histological examination to aid in differentiating DF from DFSP. Collagen triple helix repeat containing-1 (Cthrc1) was identified as a novel gene expressed in the adventitia and neointima on arterial injury. It is indicated to be a cell type-specific inhibitor of transforming growth factor-β, which in turn impacts collagen type I and III deposition, neointimal formation, and dedifferentiation of stem cells. Cthrc1 has also been shown to be highly active and potent in degrading extracellular matrix proteins and was found to be overexpressed in several malignant tumours, such as breast cancer and malignant melanoma. To our knowledge, however, expression of Cthrc1 in DFSP and DF has not been studied before.
OBJECTIVES: To assess the expression of Cthrc1 in DFSP and DF and to ascertain whether Cthrc1 is superior to antibodies traditionally used in differentiating DF from DFSP.
METHODS: Immunohistochemical staining was performed on 23 cases of DFSP and 35 cases of DF, using antibodies to Cthrc1, CD34, factor XIIIa, CD10 and stromelysin-3 (ST3).
RESULTS: Twenty-two of 23 (96%) DFSP samples were positive for Cthrc1, whereas 32 of 35 (91%) DF samples were negative. CD34 was expressed in most DFSPs (22 of 23, 96%), whereas it was completely negative in most cases of DF (29 of 35, 83%). Expression of factor XIIIa was found in most cases of DF (33 of 35, 94%), whereas it was completely absent in 21 of 23 (91%) DFSP cases. Expression of CD10 was found in most cases of DF (30 of 35, 86%), whereas it was completely absent in 13 of 23 (57%) DFSP cases. ST3 was expressed strongly in most cases of DF (32 of 35, 91%), whereas it was completely absent in 18 of 23 (78%) DFSP cases. The preferential Cthrc1 staining of DFSP in comparison with DF was statistically significant (P < 0·01).
CONCLUSIONS: We confirmed that Cthrc1 is a positive marker for DFSP and that Cthrc1 staining might be more reliable than markers traditionally used. Cthrc1 was not positive in absolutely [corrected] all cases of DFSP, and combination with CD34, factor XIIIa and ST3 immunostaining could make the distinction more reliable.

Richter P, Umbreit C, Franz M, et al.
EGF/TGFβ1 co-stimulation of oral squamous cell carcinoma cells causes an epithelial-mesenchymal transition cell phenotype expressing laminin 332.
J Oral Pathol Med. 2011; 40(1):46-54 [PubMed] Related Publications
Epithelial-mesenchymal transition (EMT) is suggested to be crucial for the development of an invasive and metastatic carcinoma cell phenotype. Therefore, the definition of this phenotype is of great clinical interest. We recently evidenced vimentin positive cells in oral squamous cell carcinoma (OSCC) invasive front expressing laminin γ2 chain mRNA implicating an EMT origin of these cells. To further elucidate the nature of these cells, we have investigated the relation between EMT criteria and laminin-332 expression in a cell culture model of transforming growth factor beta-1 (TGFβ1)/epithelial growth factor (EGF) long time co-stimulation. We demonstrate that in contrast to TGFβ1 or EGF alone, co-stimulation induces phenotype transition in OSCC cells which fulfils the criteria of EMT in terms of vimentin up-regulation and E-cadherin down-regulation on protein level as well as cell scattering. Furthermore, cells displayed a strongly enhanced invasiveness and adhesion to type I-IV collagens. Phenotype transition is accompanied by an enhanced expression of laminin-332, especially of its γ2 chain. We further analyse the expression of extracellular matrix related genes by RT-PCR profiling. With respect to strongly enhanced proteins, data confirm the EMT phenotype of co-stimulated OSCC cells and expression of laminin-332. Furthermore, alpha catenin, collagen type 16, the integrin α7 and β1 chains, and MMP11 are suggested as candidates with potential role in EMT in OSCC. In summary we are able to show that EMT in OSCC is mediated by multiple growth factors and is accompanied by laminin γ2 chain up-regulation evidencing the existence of an intermediate Vim(+) /Ln332(+) EMT phenotype as seen in situ.

Martin FT, Dwyer RM, Kelly J, et al.
Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT).
Breast Cancer Res Treat. 2010; 124(2):317-26 [PubMed] Related Publications
Bone marrow-derived mesenchymal stem cells (MSCs) are known to specifically migrate to and engraft at tumour sites. Understanding interactions between cancer cells and MSCs has become fundamental to determining whether MSC-tumour interactions should be harnessed for delivery of therapeutic agents or considered a target for intervention. Breast Cancer Cell lines (MDA-MB-231, T47D & SK-Br3) were cultured alone or on a monolayer of MSCs, and retrieved using epithelial specific magnetic beads. Alterations in expression of 90 genes associated with breast tumourigenicity were analysed using low-density array. Expression of markers of epithelial-mesenchymal transition (EMT) and array results were validated using RQ-PCR. Co-cultured cells were analysed for changes in protein expression, growth pattern and morphology. Gene expression and proliferation assays were also performed on indirect co-cultures. Following direct co-culture with MSCs, breast cancer cells expressed elevated levels of oncogenes (NCOA4, FOS), proto-oncogenes (FYN, JUN), genes associated with invasion (MMP11), angiogenesis (VEGF) and anti-apoptosis (IGF1R, BCL2). However, universal downregulation of genes associated with proliferation was observed (Ki67, MYBL2), and reflected in reduced ATP production in response to MSC-secreted factors. Significant upregulation of EMT specific markers (N-cadherin, Vimentin, Twist and Snail) was also observed following co-culture with MSCs, with a reciprocal downregulation in E-cadherin protein expression. These changes were predominantly cell contact mediated and appeared to be MSC specific. Breast cancer cell morphology and growth pattern also altered in response to MSCs. MSCs may promote breast cancer metastasis through facilitation of EMT.

Zhao ZS, Chu YQ, Ye ZY, et al.
Overexpression of matrix metalloproteinase 11 in human gastric carcinoma and its clinicopathologic significance.
Hum Pathol. 2010; 41(5):686-96 [PubMed] Related Publications
Matrix metalloproteinase 11 (stromelysin-3) has recently been reported to play a key role in human tumor progression and poor clinical outcome. The aim of this study was to investigate the significance of matrix metalloproteinase 11 expression in gastric cancer. Using real-time quantitative reverse-transcription polymerase chain reaction analysis and immunohistochemistry, we studied matrix metalloproteinase 11 expression levels in non-malignant gastric tissues and in gastric cancer tissues. The association between matrix metalloproteinase 11 expression levels and tumor stage and grade, as well as metastatic potential, was analyzed. Our results show that matrix metalloproteinase 11 expression was significantly higher in gastric cancer specimens compared with nonmalignant tissues at both transcriptional and protein levels, indicating its positive role in the development of gastric cancer. In addition, increased matrix metalloproteinase 11 expression levels were associated with advanced-stage and high-grade tumors, suggesting its involvement in the progression of gastric cancer. More importantly, increased matrix metalloproteinase 11 expression in gastric cancer specimens was correlated with increased expression of IGF-1, a molecule known to stimulate the proliferation, enhanced survival, and migration of cancer cells. Our results demonstrate that matrix metalloproteinase 11 is a novel factor in the development and progression of gastric cancer and suggest that matrix metalloproteinase 11 is a marker for advanced gastric cancer.

Sun Y, Wang L, Jiang M, et al.
Secreted phosphoprotein 1 upstream invasive network construction and analysis of lung adenocarcinoma compared with human normal adjacent tissues by integrative biocomputation.
Cell Biochem Biophys. 2010; 56(2-3):59-71 [PubMed] Related Publications
The aim of this study is to set up single molecular secreted phosphoprotein 1 (SPP1) upstream invasive network of lung adenocarcinoma. This paper proposed an integrated method based on linear programming and a decomposition procedure with integrated analysis of the significant function cluster using Kappa statistics and fuzzy heuristic clustering. Our study proved that only modules appearing in lung adenocarcinoma include cytokine module (CXCL13, GREM1_2 inhibition), cell adhesion module (COL11A1_2 activation; CDH3 inhibition), and receptor binding module (NMU activation; CXCL13, GREM1_2 inhibition), which increase the invasion of cancer cell. We compared skeletal development, signal, biological regulation, sequence variant modules between human normal adjacent tissues and lung adenocarcinoma. SPP1 skeletal development module appears in human normal adjacent tissues (COL11A1_1 activation; COL10A1 inhibition), whereas in lung adenocarcinoma (COL11A1_2, COL1A2 activation); signal module appears in human normal adjacent tissues (COL11A1_1, CXCL13, MMP11, SPINK1 activation; COL10A1, COL3A1 inhibition), whereas in lung adenocarcinoma (COL11A1_2, COL1A2, MMP12 activation; CDH3, CXCL13, GREM1_2, MMP11, SPINK1 inhibition); biological regulation module appears in human normal adjacent tissues (CXCL13, MKI67, PYCR1 activation; NEK2, SPDEF, TOP2A_2, TOX3_1 inhibition), whereas in lung adenocarcinoma (HMGB3, MKI67, NMU, PYCR1, TOX3_2 activation; CXCL13, SPDEF, TOP2A_2 inhibition); sequence variant module appears in human normal adjacent tissues (COL11A1_1, MKI67, MMP11 activation; ASPM, COL10A1, COL3A1, NEK2, TMPRSS4, TOP2A_2 inhibition), whereas in lung adenocarcinoma (COL11A1_2, COL1A2, HMMR, MKI67, MMP12 activation; ABCC3, ASPM, CDH3, MMP11, TOP2A_2 inhibition). It can be deduced that modules above in human normal adjacent tissues reflect the invasive inhibition of normal cells, whereas in lung adenocarcinoma increase the invasion of cancer cell. Our study of SPP1 upstream invasive network may be useful to identify novel and potentially targets for prognosis and therapy of lung adenocarcinoma.

Cheng CW, Yu JC, Wang HW, et al.
The clinical implications of MMP-11 and CK-20 expression in human breast cancer.
Clin Chim Acta. 2010; 411(3-4):234-41 [PubMed] Related Publications
BACKGROUND: Tumor invasiveness and metastasis in cancer progression is manifested by epigenetic abnormality. However, it remains unknown whether transcription regulation of matrix metalloproteinase-11(MMP-11) and cytoskeleton-20 (CK-20) genes for the homoeostasis of epithelial/connective interface that can enhance cell dissemination and invasion may act as alternative mutators to tumor clinicopathology.
METHODS: Paired cancerous and tumor-adjacent normal tissues from 72 breast cancer patients were assayed for the expression of MMP-11 and CK-20 by using real-time RT-PCR. The expression profiles were evaluated for the association with clinicopathological factors.
RESULTS: Breast tumor tissues displayed higher expression levels of MMP-11 and CK-20 than those of the adjacent non-cancerous tissues. Overexpression of either MMP-11 or CK-20 correlated with patients having poorly differentiated tumors (P(MMP-11)=0.01 and P(CK-20)=0.05) and lymph node metastasis (LNM) (P(MMP-11)=0.004 and P(CK-20)=0.001). A synergistic effect between MMP-11 and CK-20 on risk elevation was significant in patients with advanced tumor stage (OR=2.03, 95%CI=1.10-3.77) and LNM (OR=2.83, 95%CI=1.20-4.71). Additionally, patients lacking progesterone receptor exhibited high expression of MMP-11 and CK-20.
CONCLUSION: We demonstrate that MMP-11 and CK-20 are probable prognostic markers whose expression reflects the stages of tumor differentiation and LNM of breast cancer.

Joseph DS, Malik M, Nurudeen S, Catherino WH
Myometrial cells undergo fibrotic transformation under the influence of transforming growth factor beta-3.
Fertil Steril. 2010; 93(5):1500-8 [PubMed] Related Publications
OBJECTIVE: To examine the effect of transforming growth factor (TGF) beta3 on immortalized myometrial and leiomyoma cell lines cloned from primary cell cultures of surgical specimens, and to determine whether such treatment alters myometrial cell extracellular matrix (ECM) expression.
DESIGN: Laboratory study.
SETTING: University hospital.
PATIENT(S): Immortalized myometrial and leiomyoma cells from patients with symptomatic leiomyomata.
INTERVENTION(S): Tissue culture, followed by cellular, RNA, and protein analysis.
MAIN OUTCOME MEASURE(S): Cell proliferation, alteration in ECM component expression.
RESULT(S): Immortalized leiomyoma and myometrial cells demonstrate increased mRNA and protein production of the ECM proteins, collagen 1A1 (15.0-fold), fibronectin 1 (2.93 fold), and connective tissue growth factor (9.40-fold) with exogenous TGF-beta3 stimulation. Notably, the expression of collagen 1A1, fibronectin 1, and connective tissue growth factor in myometrial cells increase to similar expression levels as those found in leiomyoma cells. In addition, TGF-beta3 decreased production of genes involved in matrix resorption, including matrix metalloproteinase 2 (0.65-fold) and -11 (0.68-fold).
CONCLUSION(S): TGF-beta3 induced a molecular phenotype in myometrial cells that was similar to leiomyoma cells, with elevated production of ECM-related genes and decreased production of ECM degradation-related genes.

Fiorentino M, Fu L, Shi YB
Mutational analysis of the cleavage of the cancer-associated laminin receptor by stromelysin-3 reveals the contribution of flanking sequences to site recognition and cleavage efficiency.
Int J Mol Med. 2009; 23(3):389-97 [PubMed] Free Access to Full Article Related Publications
The matrix metalloproteinase stromelysin-3 (ST3) has long been implicated to play an important role in cell fate determination during normal and pathological processes. Using the thyroid hormone-dependent Xenopus laevis metamorphosis as a model, we have previously shown that ST3 is required for apoptosis during intestinal remodeling and that laminin receptor (LR) is an in vivo substrate of ST3 during this process. ST3 cleaves LR at two distinct sites that are conserved in mammalian LR. Human ST3 and LR are both associated with tumor development and cancer progression and human LR can also be cleaved by ST3, implicating a role of LR cleavage by ST3 in human cancers. Here, we carried out a series of mutational analyses on the two cleavage sites in LR. Our findings revealed that in addition to primary sequence at the cleavage site (positions P3-P3', with the cleavage occurring between P1-P1'), flanking sequences/conformation also influenced the cleavage of LR by ST3. Furthermore, alanine substitution studies led to a surprising finding that surrounding sequence and/or conformation dictated the site of cleavage in LR by ST3. These results thus have important implications in our understanding of substrate recognition and cleavage by ST3 and argue for the importance of studying ST3 cleavage in the context of full-length substrates. Furthermore, the LR cleavage mutants generated here will also be valuable tools for future studies on the role of LR cleavage by ST3 in vertebrate development and cancer progression.

Further References

Têtu B, Brisson J, Lapointe H, Bernard P
Prognostic significance of stromelysin 3, gelatinase A, and urokinase expression in breast cancer.
Hum Pathol. 1998; 29(9):979-85 [PubMed] Related Publications
This study was aimed at testing the hypothesis that the expression of proteases essentially produced by reactive stromal cells (stromelysin-3 [ST3], gelatinase A [GELA], and urokinase [uPA]) is predictive of prognosis in patients with breast cancer. This was a study of patients with node-positive and node-negative breast cancer diagnosed from 1980 to 1986 and with an average of 10 years follow-up. ST3 (665 cases), GELA, and uPA (575 cases each) expression was obtained by in situ hybridization on formalin-fixed, paraffin-embedded material using mRNA antisense probes. ST3 was expressed by 86.6% of the cases; GELA, 77.7%; and uPA, 64.7%. A significant correlation (P < .05) was found between high (more than 10%) ST3 expression and a younger age, lymph node involvement, poor nuclear grade, ductal histology, aneuploidy, and HSP-27 expression. High GELA expression was significantly associated with c-erbB2, ductal histology, and HSP-27 expression. High uPA expression correlated with poor nuclear grade, ductal histology, lack of estrogen and progesterone receptors, and p53 protein accumulation. High level of expression of all three proteases correlated significantly with each other and with cathepsin D expression by reactive stromal cells. By univariate analysis, both ST3 and uPA expression significantly predicted a shorter recurrence-free survival (ST3, P = .0199; uPA, P = .0269). By multivariate analyses, the prognostic significance was lost, most particularly at longer term. This study adds support to the concept that protease expression by reactive stromal cells is related to cancer cell characteristics but that their contribution to cancer progression is marginal.

Ahmad A, Hanby A, Dublin E, et al.
Stromelysin 3: an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression.
Am J Pathol. 1998; 152(3):721-8 [PubMed] Free Access to Full Article Related Publications
Stromelysin 3 (ST3) is a matrix metalloproteinase implicated in mammary carcinoma progression. To date, localization of ST3 expression in breast cancer by in situ hybridization and immunocytochemistry has shown that the expression of the enzyme is limited to only the stromal fibroblasts surrounding the cancer cells. We have immunostained a large group of ductal carcinoma in situ and invasive breast carcinomas using a monoclonal antibody (5ST-4A9) raised against the hemopexin-like domain of human ST3. We show that invasive lobular carcinomas express significantly less ST3 than invasive ductal carcinomas (IDCs) (P = 0.002). We also show, for the first time, that certain breast carcinoma cells that have undergone a degree of epithelial-to-mesenchymal transition, the so-called metaplastic carcinomas, can express ST3 mRNA and protein, which may in part explain the increased metastatic propensity seen in a number of these tumors. In addition, patients with IDC who had moderate to strong ST3 levels had significantly shorter disease-free survival than those with negative or weak ST3 levels (P = 0.02). Furthermore, in node-positive IDC patients, multivariate analysis revealed that ST3 level was a strong, independent prognostic parameter for disease-free survival (P = 0.005).

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