Gene Summary

Gene:MMP14; matrix metallopeptidase 14
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 protein encoded by this gene is a member of the membrane-type MMP (MT-MMP) subfamily; each member of this subfamily contains a potential transmembrane domain suggesting that these proteins are expressed at the cell surface rather than secreted. This protein activates MMP2 protein, and this activity may be involved in tumor invasion. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:matrix metalloproteinase-14
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 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.

  • Chromosome 14
  • Tissue Inhibitor of Metalloproteinase-3
  • Cell Movement
  • Lung Cancer
  • Angiogenesis
  • Transcriptional Activation
  • Stomach Cancer
  • Proteolysis
  • Xenograft Models
  • Protein Transport
  • Transcription Factors
  • Stromal Cells
  • Young Adult
  • Peritoneal Cavity
  • Protein Structure, Tertiary
  • Bladder Cancer
  • Stem Cells
  • Cancer Gene Expression Regulation
  • Urokinase-Type Plasminogen Activator
  • Neoplasm Invasiveness
  • Signal Transduction
  • Vascular Endothelial Growth Factors
  • rho GTP-Binding Proteins
  • mRNA Cleavage and Polyadenylation Factors
  • Cancer RNA
  • p21-Activated Kinases
  • rho-Associated Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Tongue Neoplasms
  • TGFB1
  • src-Family Kinases
  • Breast Cancer
  • Matrix Metalloproteinase 14
  • beta Catenin
  • Messenger RNA
  • Cervical Cancer
  • Receptors, CXCR
  • RHOA
  • YY1 Transcription Factor
  • Transfection
Tag cloud generated 11 March, 2017 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.

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

Latest Publications: MMP14 (cancer-related)

Yang J, Wang C, Zhang Z, et al.
Curcumin inhibits the survival and metastasis of prostate cancer cells via the Notch-1 signaling pathway.
APMIS. 2017; 125(2):134-140 [PubMed] Related Publications
Prostate cancer is one of the most common malignancies in men, and it urgently demands precise interventions that target the signaling pathways implicated in its initiation, progression, and metastasis. The Notch-1 signaling pathway is closely associated with the pathophysiology of prostate cancer. This study investigated the antitumor effects and mechanisms of curcumin, which is a well-known natural compound from curcuminoids, in prostate cancer cells. Viability, proliferation, and migration were analyzed in two prostate cancer cell lines, DU145 and PC3, after curcumin treatment. Whether the Notch-1 signaling pathway is involved in the antitumor effects of curcumin was examined. Curcumin inhibited the survival and proliferation of PC3 and DU145 cells in a dose- and time-dependent manner and inhibited DU145 migration. Curcumin did not affect the expression of Notch-1 or its active product NICD, but it did inhibit the expression of MT1-MMP and MMP2 proteins in DU145 cells. We found that curcumin inhibited the DNA-binding ability of NICD in DU145 cells. In conclusion, curcumin inhibited the survival and metastasis of prostate cancer cells via the Notch-1 signaling pathway.

Ezzoukhry Z, Henriet E, Piquet L, et al.
TGF-β1 promotes linear invadosome formation in hepatocellular carcinoma cells, through DDR1 up-regulation and collagen I cross-linking.
Eur J Cell Biol. 2016; 95(11):503-512 [PubMed] Related Publications
Transforming growth factor-β1 (TGF-β1) is an important player in chronic liver diseases inducing fibrogenesis and hepatocellular carcinoma (HCC) development. TGF-β1 promotes pleiotropic modifications at the cellular and matrix microenvironment levels. TGF-β1 was described to enhance production of type I collagen and its associated cross-linking enzyme, the lysyl oxidase-like2 (LOXL2). In addition, TGF-β1 and type I collagen are potent inducers of invadosomes. Indeed, type I collagen fibers induce the formation of active linear invadosomes through the discoidin domain receptor 1 (DDR1). The goal of our study was to address the role of TGF-β1 in collagen cross-linking and its impact on the formation of linear invadosomes in liver cancer cells. We first report a significant correlation between expressions of TGF-β1, and type I collagen, LOXL2, DDR1 and MT1-MMP in human HCCs. We demonstrate that TGF-β1 promotes a Smad4-dependent up-regulation of DDR1, together with LOXL2, in cultured HCC cells. Moreover, we show that LOXL2-induced collagen cross-linking enhances linear invadosome formation. Altogether, our data demonstrate that TGF-β1 favors linear invadosome formation through the expressions of both the inducers, such as collagen and LOXL2, and the components such as DDR1 and MT1-MMP of linear invadosomes in cancer cells. Meanwhile, our data uncover a new TGF-β1-dependent regulation of DDR1 expression.

Wang Y, Li J, Chen H, et al.
Down-regulation of miR-133a as a poor prognosticator in non-small cell lung cancer.
Gene. 2016; 591(2):333-7 [PubMed] Related Publications
miR-133a has been demonstrated to play an important role in tumor progression. The aim of present study was to analyze the correlation between miR-133a expression level and clinicopathologic features and its prognostic significance in non-small cell lung cancer (NSCLC). The expression of miR-133a in 104 pairs of human lung cancer tissues and adjacent normal lung tissues were analyzed by qRT-PCR. Here we show that miR-133a was down-regulated in NSCLC. The levels of miR-133a were negatively correlated with the status of N classification (N0-N1 vs. N2-N3, P=0.000), clinical stage (I-II vs. III-IV, P=0.010) and MMP-14 expression (High vs. Low, P=0.012). The patients with low miR-133a expression had shorter survival time than those with high miR-133a expression. Multivariate analysis indicated that the level of miR-133a expression was an independent prognostic indicator (P=0.012) for the survival of patients with NSCLC. In conclusion, decreased expression of miR-133a might be a potential unfavorable prognostic factor for patients with NSCLC, and further studies would be needed to prove our findings.

Sakr M, Takino T, Sabit H, et al.
miR-150-5p and miR-133a suppress glioma cell proliferation and migration through targeting membrane-type-1 matrix metalloproteinase.
Gene. 2016; 587(2):155-62 [PubMed] Related Publications
Gliomas are the most frequent primary tumors of the brain, and there is no successful treatment for highly malignant gliomas. MicroRNAs (miRNAs) are involved in a variety of biological processes. Recent studies showed that miR-150-5p and miR-133a are downregulated in various human malignancies, and one of target mRNAs was shown to be membrane-type 1 matrix metalloproteinase (MT1-MMP) mRNA. However, their detailed role in the processes of cancer remains to be determined. Here we found that miR-150-5p and miR-133a expression was significantly downregulated in glioma tissues compared with normal tissues, and that MT1-MMP expression was inversely upregulated in glioma tissues. Knockdown of MT1-MMP by specific siRNAs in U87 and U251 glioma cells induced suppression of cell proliferation and invasion/migration. Transfection of miR-150-5p or miR-133a mimics into glioma cell lines reduced MT1-MMP expression and MMP-2 activation by these cells, and cell proliferation and invasion/migration were also suppressed by it. Co-transfection of specific inhibitor oligo DNA for miR-150-5p or miR-133a abrogated miR-150-5p or miR-133a mimic's actions, respectively. These results suggest that miR-150-5p and miR-133a may suppress malignancy of gliomas by targeting MT1-MMP, and could be used as an anti-metastatic therapy for glioma patients.

Kim D, Jung J, You E, et al.
mDia1 regulates breast cancer invasion by controlling membrane type 1-matrix metalloproteinase localization.
Oncotarget. 2016; 7(14):17829-43 [PubMed] Free Access to Full Article Related Publications
Mammalian diaphanous-related formin 1 (mDia1) expression has been linked with progression of malignant cancers in various tissues. However, the precise molecular mechanism underlying mDia1-mediated invasion in cancer cells has not been fully elucidated. In this study, we found that mDia1 is upregulated in invasive breast cancer cells. Knockdown of mDia1 in invasive breast cancer profoundly reduced invasive activity by controlling cellular localization of membrane type 1-matrix metalloproteinase (MT1-MMP) through interaction with microtubule tracks. Gene silencing and ectopic expression of the active form of mDia1 showed that mDia1 plays a key role in the intracellular trafficking of MT1-MMP to the plasma membrane through microtubules. We also demonstrated that highly invasive breast cancer cells possessed invasive activity in a 3D culture system, which was significantly reduced upon silencing mDia1 or MT1-MMP. Furthermore, mDia1-deficient cells cultured in 3D matrix showed impaired expression of the cancer stem cell marker genes, CD44 and CD133. Collectively, our findings suggest that regulation of cellular trafficking and microtubule-mediated localization of MT1-MMP by mDia1 is likely important in breast cancer invasion through the expression of cancer stem cell genes.

Yang Y, Jiang Y, Wan Y, et al.
UCA1 functions as a competing endogenous RNA to suppress epithelial ovarian cancer metastasis.
Tumour Biol. 2016; 37(8):10633-41 [PubMed] Related Publications
Urothelial cancer associated 1 (UCA1) is an example of functional long noncoding RNAs involved in many biologic processes. However, little is known about the association between UCA1 expression and metastasis in epithelial ovarian cancer (EOC). Findings of this study confirmed that not only UCA1 was aberrantly upregulated in EOC tissues and cells, but also correlated with status of lymph node metastasis and FIGO stage. Furthermore, univariate and multivariate analyses showed that UCA1 was a prognostic factor for overall survival in EOC patients. In vitro, knockdown of UCA1 reduced the invasion and migration ability of EOC cells. The results showed that UCA1 could function as an endogenous sponge by directly binding to miR-485-5p. Depletion of UCA1 was involved in the downregulation of matrix metallopeptidase 14 (MMP14) expression, a target gene of miR-485-5p. In conclusion, our work indicates that UCA1 is a new prognostic biomarker for EOC, establishing a novel connection among UCA1, miR-485-5p, and MMP14 in EOC metastasis.

Zhang YH, Wang JJ, Li M, et al.
Matrix Metallopeptidase 14 Plays an Important Role in Regulating Tumorigenic Gene Expression and Invasion Ability of HeLa Cells.
Int J Gynecol Cancer. 2016; 26(3):600-6 [PubMed] Related Publications
OBJECTIVES: The objectives of this study were to investigate the functional effect of matrix metallopeptidase 14 (MMP14) on cell invasion in cervical cancer cells (HeLa line) and to study the underlying molecular mechanisms.
METHODS: Expression vector of short hairpin RNA targeting MMP14 was treated in HeLa cells, and then, transfection efficiency was verified by a florescence microscope. Transwell assay was used to investigate cell invasion ability in HeLa cells. Quantitative polymerase chain reaction and Western blotting analysis were used to detect the expression of MMP14 and relative factors in messenger RNA and protein levels, respectively.
RESULTS: Matrix metallopeptidase 14 short hairpin RNA expression vector transfection obviously decreased MMP14 expression in messenger RNA and protein levels. Down-regulation of MMP14 suppressed invasion ability of HeLa cells and reduced transforming growth factor β1 and vascular endothelial growth factor B expressions. Furthermore, MMP14 knockdown decreased bone sialoprotein and enhanced forkhead box protein L2 expression in both RNA and protein levels.
CONCLUSION: Matrix metallopeptidase 14 plays an important role in regulating invasion of HeLa cells. Matrix metallopeptidase 14 knockdown contributes to attenuating the malignant phenotype of cervical cancer cell.

Deng J, Liang H, Zhang R, et al.
Clinical and experimental role of ring finger protein 180 on lymph node metastasis and survival in gastric cancer.
Br J Surg. 2016; 103(4):407-16 [PubMed] Related Publications
BACKGROUND: The hypermethylation of ring finger protein (RNF) 180 DNA promoter is significantly associated with lymph node metastasis of gastric cancer. The present study explored the potential mechanism of RNF180-regulated lymph node metastasis of gastric cancer.
METHODS: Associations between clinicopathological and survival data and RNF180 expression in gastric cancer tissues were analysed. The effects of RNF180 re-expression on gastric cancer cells were determined by means of proliferation, invasion, growth and lymphangiogenesis assays. A genome microarray was used to find potential target genes associated with lymphatic metastasis of gastric cancer cells regulated by RNF180.
RESULTS: RNF180 was silenced or downregulated in 99 (73·9 per cent) of 134 gastric cancer tissues compared with 41·8 per cent of paired non-tumour tissues from patients. As an independent prognostic indicator of gastric cancer, RNF180 expression in gastric cancer tissues was negatively related to the number of metastatic lymph nodes. RNF180 was also downregulated in all seven gastric cancer cell lines examined. The re-expression of RNF180 in gastric cancer cells inhibited colony formation, proliferation, migration and invasion in vitro; re-expression of RNF180 also suppressed tumour growth and lymphangiogenesis in mice. Furthermore, re-expression of RNF180 downregulated the expression of hepatocyte growth factor, matrix metalloproteinase (MMP) 2, MMP-14, vascular endothelial growth factor C/D and chemokine receptor 7 in gastric cancer cells; it also downregulated the expression of podoplanin in tumour tissue of nude mice.
CONCLUSION: RNF180 appears to act as a suppressor gene that inhibits lymph node metastasis in gastric cancer.
SURGICAL RELEVANCE: Biological mechanisms that lead to lymph node metastasis in gastric cancer have not been clarified. Ring finger protein (RNF) 180 has been shown to participate in the processes of lymph node metastasis in several human malignancies. In this study, silencing or downregulation of RNF180 expression was significantly associated with lymph node metastasis of gastric cancer. In vitro, RNF180 expression suppressed the common biological characteristics of gastric cancer cells (HGC-27), including proliferation, invasion, lymphangio genesis and chemotaxis. RNF180 expression also inhibited tumour growth and tumour lymphangiogenesis in vivo. These results show that RNF180 is capable of inhibiting lymph node metastasis of gastric cancer by suppressing the intracellular activation of malignant molecular signals. Therefore, RNF180 could be considered as a promising biomarker for evaluation of the tumour aggressiveness and may be a target for future therapeutic intervention.

Di D, Chen L, Wang L, et al.
Downregulation of human intercellular adhesion molecule-1 attenuates the metastatic ability in human breast cancer cell lines.
Oncol Rep. 2016; 35(3):1541-8 [PubMed] Related Publications
Intercellular adhesion molecule-1 (ICAM-1) is a cell surface glycoprotein that belongs to immunoglobulin superfamily and plays an important role in tumor cell expansion or metastasis. However, the detailed mechanisms of ICAM-1 in breast cancer remain unclear. In this study, we evaluated the expression level of ICAM-1 in breast cancer using tissue microarray and clinical tissue specimens by immunohistochemical method, and the results revealed that ICAM-1 is highly expressed in the breast cancer tissues. To investigate whether ICAM-1 can affect the metastasis ability in breast cancer, we knocked down ICAM-1 expression in breast cancer cell line MCF-7 by using lentivirus-mediated RNA interference (RNAi). As a result, we stably silenced ICAM-1 expression in MCF-7 cells by infection with lentivirus expressing green fluorescent protein (GFP), the change of metastatic ability of MCF-7 cells was assessed by wound-healing assay, Transwell assay or clone formation assay. Our results showed that silencing of ICAM-1 can inhibit the metastatic ability of MCF-7 cell lines in vitro significantly, and the decreased migration and invasion was accompanied by a reduction of MMP-14. These results implying that ICAM-1 might be involved in the progression of breast cancer metastasis and lentivirus-mediated silencing of ICAM-1 might be a potential therapeutic approach for the treatment of breast cancer.

Goertzen CG, Dragan M, Turley E, et al.
KISS1R signaling promotes invadopodia formation in human breast cancer cell via β-arrestin2/ERK.
Cell Signal. 2016; 28(3):165-76 [PubMed] Related Publications
Kisspeptins (KPs), peptide products of the KISS1 gene are endogenous ligands for the kisspeptin receptor (KISS1R), a G protein-coupled receptor. In numerous cancers, KISS1R signaling plays anti-metastatic roles. However, we have previously shown that in breast cancer cells lacking the estrogen receptor (ERα), kisspeptin-10 stimulates cell migration and invasion by cross-talking with the epidermal growth factor receptor (EGFR), via a β-arrestin-2-dependent mechanism. To further define the mechanisms by which KISS1R stimulates invasion, we determined the effect of down-regulating KISS1R expression in triple negative breast cancer cells. We found that depletion of KISS1R reduced their mesenchymal phenotype and invasiveness. We show for the first time that KISS1R signaling induces invadopodia formation and activation of key invadopodia proteins, cortactin, cofilin and membrane type I matrix metalloproteases (MT1-MMP). Moreover, KISS1R stimulated invadopodia formation occurs via a new pathway involving a β-arrestin2 and ERK1/2-dependent mechanism, independent of Src. Taken together, our findings suggest that targeting the KISS1R signaling axis might be a promising strategy to inhibit invasiveness and metastasis.

Heo SH, Lee JY, Yang KM, Park KS
ELK3 Expression Correlates With Cell Migration, Invasion, and Membrane Type 1-Matrix Metalloproteinase Expression in MDA-MB-231 Breast Cancer Cells.
Gene Expr. 2015; 16(4):197-203 [PubMed] Related Publications
ELK3 is a member of the Ets family of transcription factors. Its expression is associated with angiogenesis, vasculogenesis, and chondrogenesis. ELK3 inhibits endothelial migration and tube formation through the regulation of MT1-MMP transcription. This study assessed the function of ELK3 in breast cancer (BC) cells by comparing its expression between basal and luminal cells in silico and in vitro. In silico analysis showed that ELK3 expression was higher in the more aggressive basal BC cells than in luminal BC cells. Similarly, in vitro analysis showed that ELK3 mRNA and protein expression was higher in basal BC cells than in normal cells and luminal BC cells. To investigate whether ELK3 regulates basal cell migration or invasion, knockdown was achieved by siRNA in the basal BC cell line MDA-MB-231. Inhibition of ELK3 expression decreased cell migration and invasion and downregulated MT1-MMP, the expression of which is positively correlated with tumor cell invasion. In silico analysis revealed that ELK3 expression was associated with that of MT1-MMP in several BC cell lines (0.98 Pearson correlation coefficient). Though MT1-MMP expression was upregulated upon ELK3 nuclear translocation, ELK3 did not directly bind to the 1.3-kb promoter region of the MT1-MMP gene. These results suggest that ELK3 plays a positive role in the metastasis of BC cells by indirectly regulating MT1-MMP expression.

Alexiades NG, Auffinger B, Kim CK, et al.
MMP14 as a novel downstream target of VEGFR2 in migratory glioma-tropic neural stem cells.
Stem Cell Res. 2015; 15(3):598-607 [PubMed] Free Access to Full Article Related Publications
Neural stem cell (NSC)-based carriers have been presented as promising therapeutic tools for the treatment of infiltrative brain tumors due to their intrinsic tumor homing property. They have demonstrated the ability to migrate towards distant tumor microsatellites and effectively deliver the therapeutic payload, thus significantly improving survival in experimental animal models for brain tumor. Despite such optimistic results, the efficacy of NSC-based anti-cancer therapy has been limited due to the restricted tumor homing ability of NSCs. To examine this issue, we investigated the mechanisms of tumor-tropic migration of an FDA-approved NSC line, HB1.F3.CD, by performing a gene expression analysis. We identified vascular endothelial growth factor-A (VEGFA) and membrane-bound matrix metalloproteinase (MMP14) as molecules whose expression are significantly elevated in migratory NSCs. We observed increased expression of VEGF receptor 2 (VEGFR2) in the focal adhesion complexes of migratory NSCs, with downstream activation of VEGFR2-dependent kinases such as p-PLCγ, p-FAK, and p-Akt, a signaling cascade reported to be required for cellular migration. In an in vivo orthotopic glioma xenograft model, analysis of the migratory trail showed that NSCs maintained expression of VEGFR2 and preferentially migrated within the perivascular space. Knockdown of VEGFR2 via shRNAs led to significant downregulation of MMP14 expression, which resulted in inhibited tumor-tropic migration. Overall, our results suggest, the involvement of VEGFR2-regulated MMP14 in the tumor-tropic migratory behavior of NSCs. Our data warrant investigation of MMP14 as a target for enhancing the migratory properties of NSC carriers and optimizing the delivery of therapeutic payloads to disseminated tumor burdens.

Wu J, Zhang XX, Sun QM, et al.
β-Asarone inhibits gastric cancer cell proliferation.
Oncol Rep. 2015; 34(6):3043-50 [PubMed] Related Publications
β-Asarone is the main volatile oil of Chinese herb Rhizoma Acori Tatarinowii. It exhibits a wide range of biological activities in many human organs. However, few studies have investigated the effect of β-asarone on gastric cancer. The present study investigated the effect of β-asarone on the proliferation and apoptosis of three types of differentiated human gastric cancer cell lines (SGC-7901, BGC-823 and MKN-28) in vitro as well as the related molecular mechanisms. Methyl thiazolyl tetrazolium assay, Annexin V/PI double staining, immunofluorescence test and transmission electron microscopy all confirmed that β-asarone had an obvious dose-dependent inhibitive effect on the proliferation of human gastric cancer cells and induced apoptosis of the cell lines. Transwell invasion, wound-healing and matrix‑cell adhesion experiments confirmed that β-asarone inhibited the invasion, migration and adhesion of human gastric cancer BGC-823 cells. Quantitative real-time PCR and western blotting found that β-asarone significantly activated caspase-3, caspase-8, caspase-9, Bax, Bak and suppressed Bcl-2, Bcl-xL and survivin activity. Moreover, β-asarone increased the expression of RECK, E-cadherin and decreased the expression of MMP-2, MMP-9, MMP-14 and N-cadherin. The present study demonstrated that β-asarone effectively inhibits the proliferation of human gastric cancer cells, induces their apoptosis and decreased the invasive, migratory and adhesive abilities.

Takino T, Nakada M, Li Z, et al.
Tip60 regulates MT1-MMP transcription and invasion of glioblastoma cells through NF-κB pathway.
Clin Exp Metastasis. 2016; 33(1):45-52 [PubMed] Related Publications
A histone acetyltransferase Tat-interacting protein 60 kDa (Tip60) regulates the DNA damage response by acetylating histone and remodeling chromatin. In addition to histone acetyltransferase activity, Tip60 is known to regulate a variety of cellular functions, including gene expression, DNA damage response, cell migration and apoptosis. Lower expression of Tip60 is observed in lymphomas, melanomas, breast, colon, and lung cancer. It is widely accepted that Tip60 functions as a tumor suppressor. However, a role of Tip60 in gliomas still remains unclear. In this study, we investigated the role of Tip60 in the malignant behavior of human gliomas. By quantitative RT-PCR analysis using fresh human brain tumor tissues from 55 patients, we found that lower Tip60 expression and higher membrane-type 1 matrix metalloproteinase (MT1-MMP) expression are associated with advanced tumor grade in glioma tissues. Knockdown of Tip60 in glioblastoma cells promoted cell adhesion, spreading and MT1-MMP transcription and thereby invasion, which was suppressed by inhibition of MT1-MMP and nuclear factor-kappa B (NF-κB) activity. We demonstrate for the first time that tumor suppressor Tip60 down-regulates cell adhesion and MT1-MMP expression and thereby invasion of glioblastoma cells by suppressing NF-κB pathway.

Trombetta-Lima M, Winnischofer SM, Demasi MA, et al.
Isolation and characterization of novel RECK tumor suppressor gene splice variants.
Oncotarget. 2015; 6(32):33120-33 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme is the most common and lethal of the central nervous system glial-derived tumors. RECK suppresses tumor invasion by negatively regulating at least three members of the matrix metalloproteinase family: MMP-9, MMP-2, and MT1-MMP. A positive correlation has been observed between the abundance of RECK expression in tumor samples and a more favorable prognosis for patients with several types of tumors. In the present study, novel alternatively spliced variants of the RECK gene: RECK-B and RECK-I were isolated by RT-PCR and sequenced. The expression levels and profiles of these alternative RECK transcripts, as well as canonical RECK were determined in tissue samples of malignant astrocytomas of different grades and in a normal tissue RNA panel by qRT-PCR. Our results show that higher canonical RECK expression, accompanied by a higher canonical to alternative transcript expression ratio, positively correlates with higher overall survival rate after chemotherapeutic treatment of GBM patients. U87MG and T98G cells over-expressing the RECK-B alternative variant display higher anchorage-independent clonal growth and do not display modulation of, respectively, MMP-2 and MMP-9 expression. Our findings suggest that RECK transcript variants might have opposite roles in GBM biology and the ratio of their expression levels may be informative for the prognostic outcome of GBM patients.

Shaverdashvili K, Zhang K, Osman I, et al.
MT1-MMP dependent repression of the tumor suppressor SPRY4 contributes to MT1-MMP driven melanoma cell motility.
Oncotarget. 2015; 6(32):33512-22 [PubMed] Free Access to Full Article Related Publications
Metastatic melanoma is the deadliest of all skin cancers. Despite progress in diagnostics and treatment of melanoma, the prognosis for metastatic patients remains poor. We previously showed that Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) is one of the drivers of melanoma metastasis. Classically, MT1-MMP regulates a verity of cellular functions including cell-to-cell interaction and cell-to-matrix communication. Recently, MT1-MMP has been found to also modulate gene expression. To specifically assess MT1-MMP dependent gene regulation in melanoma, microarray gene expression analysis was performed in a melanoma cell line whose metastatic properties depend on the activity of MT1-MMP. We identified the tumor suppressor gene SPRY4 as a new transcriptional target of MT1-MMP that is negatively regulated by the protease. Knockdown of MT1-MMP enhances SPRY4 expression at the mRNA and protein level. SPRY4 expression inversely correlates with that of MT1-MMP in melanoma samples and importantly, correlates with melanoma patient survival. SPRY4 modulates MT1-MMP dependent cell migration such that inhibition of SPRY4 rescues cell migration that has been impaired by MT1-MMP knock down. MT1-MMP decreases SPRY4 in part through an MMP2/RAC1 axis we previously show promotes cell motility downstream of MT1-MMP. These results identify the tumor suppressor SPRY4 as a novel molecular effector of MT1-MMP affecting melanoma cell motility.

Ebisawa M, Iwano H, Nishikawa M, et al.
Significance of caveolin-1 and matrix metalloproteinase 14 gene expression in canine mammary tumours.
Vet J. 2015; 206(2):191-6 [PubMed] Related Publications
Canine mammary tumours (CMTs) are the most common neoplasms affecting female dogs. There is an urgent need for molecular biomarkers that can detect early stages of the disease in order to improve accuracy of CMT diagnosis. The aim of this study was to examine whether caveolin-1 (Cav-1) and matrix metalloproteinase 14 (MMP14) are associated with CMT histological malignancy and invasion. Sixty-five benign and malignant CMT samples and six normal canine mammary glands were analysed using quantitative reverse transcription-polymerase chain reaction. Cav-1 and MMP14 genes were highly expressed in CMT tissues compared to normal tissues. Cav-1 especially was overexpressed in malignant and invasive CMT tissues. When a CMT cell line was cultured on fluorescent gelatin-coated coverslips, localisation of Cav-1 was observed at invadopodia-mediated degradation sites of the gelatin matrix. These findings suggest that Cav-1 may be involved in CMT invasion and that the markers may be useful for estimating CMT malignancy.

Qiu H, Tang X, Ma J, et al.
Notch1 Autoactivation via Transcriptional Regulation of Furin, Which Sustains Notch1 Signaling by Processing Notch1-Activating Proteases ADAM10 and Membrane Type 1 Matrix Metalloproteinase.
Mol Cell Biol. 2015; 35(21):3622-32 [PubMed] Free Access to Full Article Related Publications
Notch1 is an evolutionarily conserved transmembrane receptor involved in melanoma growth. Notch1 is first cleaved by furin in the Golgi apparatus to produce the biologically active heterodimer. Following ligand binding, Notch1 is cleaved at the cell membrane by proteases such as ADAM10 and -17 and membrane type 1 matrix metalloproteinase (MT1-MMP), the latter of which we recently identified as a novel protease involved in Notch1 processing. The final cleavage is γ-secretase dependent and releases the active Notch intracellular domain (NIC). We now demonstrate that Notch1 directly regulates furin expression. Aside from activating Notch1, furin cleaves and activates several proteases, including MT1-MMP, ADAM10, and ADAM17. By chromatin immunoprecipitation and a reporter assay, we demonstrate that Notch1 binds at position -1236 of the furin promoter and drives furin expression. The Notch1-dependent enhancement of furin expression increases the activities of MT1-MMP and ADAM10 but not that of ADAM17, as demonstrated by short hairpin RNA (shRNA) knockdown of furin, and promotes the cleavage of Notch1 itself. These data highlight a novel positive-feedback loop whereby Notch1-dependent furin expression can induce Notch1 signaling by increasing Notch1 processing and by potentiating the activity of the proteases responsible for Notch1 activation. This leads to Notch1 signal amplification, which can promote melanoma tumor growth and progression, as demonstrated by the inhibition of cell migration and invasion upon furin inhibition downstream of Notch1. Disruption of such feedback signaling might represent an avenue for the treatment of melanoma.

Mulens-Arias V, Rojas JM, Pérez-Yagüe S, et al.
Polyethylenimine-coated SPION exhibits potential intrinsic anti-metastatic properties inhibiting migration and invasion of pancreatic tumor cells.
J Control Release. 2015; 216:78-92 [PubMed] Related Publications
Due to its aggressive behavior, pancreatic cancer is one of the principal causes of cancer-related deaths. The highly metastatic potential of pancreatic tumor cells demands the development of more effective anti-metastatic approaches for this disease. Although polyethylenimine-coated superparamagnetic iron oxide nanoparticles (PEI-coated SPIONs) have been studied for their utility as transfection agents, little is known of their effect on tumor cell biology. Here we demonstrated that PEI-coated SPIONs have potent inhibitory effects on pancreatic tumor cell migration/invasion, through inhibition of Src kinase and decreased expression of MT1-MMP and MMP2 metalloproteinases. When treated with PEI-coated SPIONs, the pancreatic tumor cell line Pan02 showed reduced invadosome density and thus, a decrease in their ability to invade through basement membrane. These nanoparticles temporarily downmodulated microRNA-21, thereby upregulating the cell migration inhibitors PTEN, PDCD4 and Sprouty-1. PEI-coated SPIONs thus show intrinsic, possibly anti-metastatic properties for modulating pancreatic tumor cell migration machinery, which indicates their potential as anti-metastatic agents for treatment of pancreatic cancer.

Xiong X, Sun D, Chai H, et al.
MiR-145 functions as a tumor suppressor targeting NUAK1 in human intrahepatic cholangiocarcinoma.
Biochem Biophys Res Commun. 2015; 465(2):262-9 [PubMed] Related Publications
The dysregulation of micro (mi)RNAs is associated with cancer development. The miRNA miR-145 is downregulated in intrahepatic cholangiocarcinoma (ICC); however, its precise role in tumor progression has not yet been elucidated. Novel (nua) kinase family (NUAK)1 functions as an oncogene in various cancers and is a putative target of miR-145 regulation. In this study, we investigated the regulation of NUAK1 by miR-145 in ICC. We found that miR-145 level was significantly decreased in ICC tissue and cell lines, which corresponded with an increase in NUAK1 expression. NUAK1 was found to be a direct target of miR-145 regulation. The overexpression of miR-145 in ICC cell lines inhibited proliferation, growth, and invasion by suppressing NUAK1 expression, which was associated with a decrease in Akt signaling and matrix metalloproteinase protein expression. Similar results were observed by inhibiting NUAK1 expression. These results demonstrate that miR-145 can prevent ICC progression by targeting NUAK1 and its downstream effectors, and can therefore be useful for clinical diagnosis and targeted therapy of ICC.

Li YY, Zhou CX, Gao Y
Moesin regulates the motility of oral cancer cells via MT1-MMP and E-cadherin/p120-catenin adhesion complex.
Oral Oncol. 2015; 51(10):935-43 [PubMed] Related Publications
OBJECTIVE: The present study aimed to clarify the role of Moesin in oral squamous cell carcinoma (OSCC) progression, especially in regulation of cell motility.
MATERIALS AND METHODS: Immunohistochemistry and western blotting were used to investigate the expression of Moesin, E-cadherin, p120-catenin and MT1-MMP in normal epithelia, dysplasia and OSCCs. Then, Moesin was knockdown by siRNA in OSCC cell lines, WSU-HN6 and CAL27, and the biological role of Moesin in cell adhesion and motility was evaluated by transwell system, cell spreading and aggregation assays. The interactions between Moesin, MT1-MMP and E-cadherin/p120-catenin complex were determined by co-immunoprecipitation and immunofluorescence.
RESULTS: Moesin expression was found decreased in the membrane and increased in cytoplasm during the malignant transformation of oral epithelia, and cytoplasmic overexpression of Moesin correlated with nodal metastasis and poor prognosis of OSCCs. Furthermore, Moesin-silencing induced an increased cell-cell adhesion but decreased invasiveness, which was subsequently demonstrated might due to Moesin-mediated E-cadherin and p120-catenin interaction. Meantime, Moesin-silencing significantly down-regulated MT1-MMP expression, accompanied by reduced cell motility and impaired filopodia formation, which was also observed when MT1-MMP knockdown by RNAi or tissue inhibitor (TIMP2), indicating the involvement of MT1-MMP in Moesin-mediated cell motility. Finally, the relationship between Moesin, E-cadherin and MT1-MMP was confirmed in OSCC tissue samples.
CONCLUSION: Taken together, our results indicate Moesin may regulate cell motility through its interactions with MT1-MMP and E-cadherin/p120-catenin adhesion complex and cytoplasmic expression of Moesin correlates with nodal metastasis and poor prognosis of OSCCs, indicating Moesin may be a potential candidate for targeted gene therapy for OSCCs.

Zhu D, Ye M, Zhang W
E6/E7 oncoproteins of high risk HPV-16 upregulate MT1-MMP, MMP-2 and MMP-9 and promote the migration of cervical cancer cells.
Int J Clin Exp Pathol. 2015; 8(5):4981-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: E6 and E7 of high risk human papillomavirus 16 (HPV16) were reported to correlate with the cervical cancer (CC). And the presence of matrix metalloproteinases (MMPs) has also been indicated to be associated with CC.
METHODS: The present study investigated the expression of MMPs (MT1-MMP, MMP-2 and MMP-9) in CC cells with HPV16-E6/E7 oncoprotein(s) negative or positive, and then determined the regulation of HPV16-E6/E7 oncoproteins on the expression of MMPs (MT1-MMP, MMP-2 and MMP-9) and the migration of cervical cancer Caski and SiHa cells with RNAi technology.
RESULTS: It was demonstrated that the overexpression or the knockdown of HPV16-E6/E7 promoted or reduced MT1-MMP, MMP-2 and MMP-9 in CC cells. And the HPV16-E6, -E7 or -E6E7 influenced the migration of CC cells. The overexpression or the knockdown of them promoted or inhibited the migration of C33A or Caski/SiHa cells. Moreover, the chemical inhibition of MMP-2 or MMP-9 significantly reduced the migration of CC Caski or SiHa cells.
CONCLUSIONS: Our results demonstrated that the E6-HPV16 or E7-HPV16 promoted the activity of MMP-2/9, and contributed to the migration of cervical cells.

Tsigkou A, Reis FM, Ciarmela P, et al.
Expression Levels of Myostatin and Matrix Metalloproteinase 14 mRNAs in Uterine Leiomyoma are Correlated With Dysmenorrhea.
Reprod Sci. 2015; 22(12):1597-602 [PubMed] Related Publications
Uterine leiomyoma is the most common benign neoplasm of female reproductive system, found in about 50% of women in reproductive age. The mechanisms of leiomyoma growth include cell proliferation, which is modulated by growth factors, and deposition of extracellular matrix (ECM). Activin A and myostatin are growth factors that play a role in proliferation of leiomyoma cells. Matrix metalloproteinases (MMPs) are known for their ability to remodel the ECM in different biological systems. The aim of this study was to evaluate the expression levels of activin βA-subunit, myostatin, and MMP14 messenger RNAs (mRNAs) in uterine leiomyomas and the possible correlation of these factors with clinical features of the disease. Matrix metalloproteinase 14 was highly expressed in uterine leiomyoma and correlated with myostatin and activin A mRNA expression. Moreover, MMP14 and myostatin mRNA expression correlated significantly and directly with the intensity of dysmenorrhea. Overall, the present findings showed that MMP14 mRNA is highly expressed in uterine leiomyoma, where it correlates with the molecular expression of growth factors and is further increased in cases of intense dysmenorrhea.

Arndt A, Kraft K, Wardelmann E, Steinestel K
Lack of Association between Membrane-Type 1 Matrix Metalloproteinase Expression and Clinically Relevant Molecular or Morphologic Tumor Characteristics at the Leading Edge of Invasive Colorectal Carcinoma.
Biomed Res Int. 2015; 2015:185404 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is one of the leading causes of death from cancer in the western world, but tumor biology and clinical course show great interindividual variation. Molecular and morphologic tumor characteristics, such as KRAS/BRAF mutation status, mismatch repair (MMR) protein expression, tumor growth pattern, and tumor cell budding, have been shown to be of key therapeutic and/or prognostic relevance in CRC. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a membrane-anchored zinc-binding endopeptidase that is expressed at the leading edge of various invasive carcinomas and promotes tumor cell invasion through degradation of the extracellular matrix. The aim of this study was to investigate possible associations between MT1-MMP expression and molecular tumor characteristics as well as morphologic features of tumor aggressiveness in a consecutive series of 79 CRC tissue samples. However, although MT1-MMP was expressed in 41/79 samples (52%), there was no significant association between MT1-MMP expression and KRAS/BRAF mutation status, MMR protein expression, presence of lymphovascular invasion, tumor growth pattern, tumor-infiltrating lymphocytes, or tumor cell budding in our sample cohort (P > 0.05). Thus, we conclude that although MT1-MMP may play a role in CRC invasion, it is not of key relevance to the current models of CRC invasion and aggressiveness.

Xiang X, Mei H, Zhao X, et al.
miRNA-337-3p suppresses neuroblastoma progression by repressing the transcription of matrix metalloproteinase 14.
Oncotarget. 2015; 6(26):22452-66 [PubMed] Free Access to Full Article Related Publications
Recent evidence shows the emerging roles of endogenous microRNAs (miRNAs) in repressing gene transcription. However, the miRNAs inhibiting the transcription of matrix metalloproteinase 14 (MMP-14), a membrane-anchored MMP crucial for the tumorigenesis and aggressiveness, still remain largely unknown. In this study, through mining computational algorithm program and genome-wide Argonaute profiling dataset, we identified one binding site of miRNA-337-3p (miR-337-3p) within the MMP-14 promoter. We demonstrated that miR-337-3p was under-expressed and inversely correlated with MMP-14 expression in clinical specimens and cell lines of neuroblastoma (NB), the most common extracranial solid tumor in childhood. Patients with high miR-337-3p expression had greater survival probability. miR-337-3p suppressed the promoter activity, nascent transcription, and expression of MMP-14, resulting in decreased levels of vascular endothelial growth factor, in cultured NB cell lines. Mechanistically, miR-337-3p recognized its binding site and recruited Argonaute 2 to facilitate the enrichment of repressive epigenetic markers and decrease the binding of RNA polymerase II and specificity protein 1 on the MMP-14 promoter. Gain- and loss-of-function studies demonstrated that miR-337-3p suppressed the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo. In addition, restoration of MMP-14 expression rescued the NB cells from changes in these biological features. Taken together, these data indicate that miR-337-3p directly binds the MMP-14 promoter to repress its transcription, thus suppressing the progression of NB.

Li T, Xie J, Shen C, et al.
Amplification of Long Noncoding RNA ZFAS1 Promotes Metastasis in Hepatocellular Carcinoma.
Cancer Res. 2015; 75(15):3181-91 [PubMed] Related Publications
Despite progress in the diagnostics and treatment of hepatocellular carcinoma (HCC), its prognosis remains poor. In this study, we globally assessed long noncoding RNAs (lncRNA) for contributions to HCC using publicly available microarray data, in vitro and in vivo assays. Here, we report that ZFAS1, encoding a lncRNA that is frequently amplified in HCC, is associated with intrahepatic and extrahepatic metastasis and poor prognosis of HCC. ZFAS1 functions as an oncogene in HCC progression by binding miR-150 and abrogating its tumor-suppressive function in this setting. miR-150 repressed HCC cell invasion by inhibiting ZEB1 and the matrix metalloproteinases MMP14 and MMP16. Conversely, ZFAS1 activated ZEB1, MMP14, and MMP16 expression, inhibiting these effects of miR-150. Our results establish a function for ZFAS1 in metastatic progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of HCC.

Ulasov I, Borovjagin AV, Kaverina N, et al.
MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo.
Cancer Lett. 2015; 365(2):240-50 [PubMed] Related Publications
MMP14 (MT1-MMP) is a cell membrane-associated proteinase of the extracellular matrix, whose biological roles vary from angiogenesis to cell proliferation and survival. We recently found a direct correlation between MMP14 expression levels in brain tumors of glioma patients and the disease progression. By using gene silencing as an experimental approach we found that MMP14 knockdown decreases production of pro-angiogenic factors such as VEGF and IL8 and thereby suppresses angiogenesis in glioma tumors. Although the clinical relevance of MMP14 down-regulation and its possible implications for glioma therapy in humans remain unclear, we observed a significant improvement in animal survival upon down-regulation of MMP14 in murine intracranial glioma xenografts infected with MMP14 shRNA-expressing CRAd. We further found that down-regulation of MMP14 in gliomas by combinational treatment with CRAd-S-5/3 and Marimastat, a chemical inhibitor of metalloproteinases, augments suppression of pro-angiogenic factors, caused by the replication-competent adenovirus. We also demonstrated that delivery of MMP14-targeting shRNA by a fiber-modified adenoviral vector to the glioma cells effectively suppresses their proliferation in vitro and in vivo. Thus our data indicate that inhibition of MMP14 expression in tumors in combination with glioma virotherapy could be effectively utilized to suppress angiogenesis and neovascularization of glioma tumors by decreasing production of pro-angiogenic factors.

Zhao J, Kong Z, Xu F, Shen W
A role of MMP-14 in the regulation of invasiveness of nasopharyngeal carcinoma.
Tumour Biol. 2015; 36(11):8609-15 [PubMed] Related Publications
Although matrix metalloproteinase 14 (MMP-14) has been shown to play a substantial role in the carcinogenesis of some types of cancer, its involvement in the pathogenesis of nasopharyngeal carcinoma (NPC) has not been reported. Here, we analyzed MMP-14 levels in the NPC specimens from patients and compared with the paired normal nasopharynx (NNP) tissues. We found that NPC had significantly higher messenger RNA (mRNA) and protein levels of MMP-14. Moreover, higher levels of MMP-14 correlated with more advanced status of clinical stage and lymphatic metastasis. In vitro, MMP-14 levels determined the potential of invasiveness of NPC cells, possibly through induction of EMT-associated genes. Our data thus highlight MMP-14 as a novel therapeutic target for NPC.

Li Y, Kuscu C, Banach A, et al.
miR-181a-5p Inhibits Cancer Cell Migration and Angiogenesis via Downregulation of Matrix Metalloproteinase-14.
Cancer Res. 2015; 75(13):2674-85 [PubMed] Free Access to Full Article Related Publications
Upregulation of matrix metalloproteinase MMP-14 (MT1-MMP) is associated with poor prognosis in cancer patients, but it is unclear how MMP-14 becomes elevated in tumors. Here, we show that miR-181a-5p is downregulated in aggressive human breast and colon cancers where its levels correlate inversely with MMP-14 expression. In clinical specimens, enhanced expression of MMP-14 was observed in cancer cells located at the invasive front of tumors where miR-181a-5p was downregulated relative to adjacent normal cells. Bioinformatics analyses defined a potential miR-181a-5p response element within the 3'-untranslated region of MMP-14 that was validated in reporter gene experiments. Ectopic miR-181a-5p reduced MMP-14 expression, whereas miR-181a-5p attenuation elevated MMP-14 expression. In support of a critical relationship between these two genes, miR-181a-5p-mediated reduction of MMP-14 levels was sufficient to decrease cancer cell migration, invasion, and activation of pro-MMP-2. Furthermore, this reduction in MMP-14 levels was sufficient to reduce in vivo invasion and angiogenesis in chick chorioallantoic membrane assays. Taken together, our results establish the regulation of MMP-14 in cancers by miR-181a-5p through a posttranscriptional mechanism, and they further suggest strategies to elevate miR-181a-5p to prevent cancer metastasis.

You L, Wang Z, Li H, et al.
The role of STAT3 in autophagy.
Autophagy. 2015; 11(5):729-39 [PubMed] Free Access to Full Article Related Publications
Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the classic autophagy model and also into cancer therapy, especially for the emerging targeted therapy, because a series of targeted agents execute antitumor activities via blocking STAT3 signaling, which inevitably affects the autophagy pathway. Here, we review several of the representative studies and the current understanding in this particular field.

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