Gene Summary

Gene:MMP13; matrix metallopeptidase 13
Aliases: CLG3, MANDP1, MMP-13
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. The protein encoded by this gene cleaves type II collagen more efficiently than types I and III. It may be involved in articular cartilage turnover and cartilage pathophysiology associated with osteoarthritis. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:collagenase 3
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
Show (26)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 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.

  • Immunohistochemistry
  • Chromosome 11
  • Stomach Cancer
  • TIMP1
  • Oligonucleotide Array Sequence Analysis
  • Thyroid Cancer
  • S100 Proteins
  • Genetic Predisposition
  • Single Nucleotide Polymorphism
  • Enzymologic Gene Expression Regulation
  • MMP1
  • Gene Expression
  • Messenger RNA
  • Collagenases
  • Protein Kinase C
  • Squamous Cell Carcinoma
  • Tumor Burden
  • Cell Movement
  • Transcriptome
  • Signal Transduction
  • Cell Proliferation
  • p38 Mitogen-Activated Protein Kinases
  • Transcription Factors
  • Stromal Cells
  • Transforming Growth Factor beta
  • Disease Progression
  • Matrix Metalloproteinases
  • Sequence Analysis
  • Gene Expression Profiling
  • Breast Cancer
  • Substrate Specificity
  • Bone Cancer
  • Western Blotting
  • Up-Regulation
  • Neoplasm Invasiveness
  • Tumor Suppressor Proteins
  • MMP9
  • Cancer Gene Expression Regulation
  • Matrix Metalloproteinase 13
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: MMP13 (cancer-related)

Gao P, Yang JL, Zhao H, et al.
Common polymorphism in the MMP-13 gene may contribute to the risk of human cancers: a meta-analysis.
Tumour Biol. 2014; 35(10):10137-48 [PubMed] Related Publications
Cancer was viewed to be driven by accumulating genetic abnormalities that generally include chromosomal abnormalities, mutations in tumor-suppressor genes, and oncogenes. The aim of this meta-analysis was to systematically summarize the possible associations between MMP-13 rs2252070 A>G variant and cancer risks. We systematically reviewed studies focusing on MMP-13 polymorphisms with human cancer susceptibility that were published before April 30, 2014. Relevant articles were identified through research of PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CBM, and CNKI databases. All analyses were calculated using the Version 12.0 STATA software. Odds ratios (OR) and 95 % confidence interval (95 % CI) were calculated. Eleven independent case-control studies were included in the meta-analysis, which involved 3,465 patients with cancers and 4,073 healthy controls. The results identified a positive association between rs2252070 A>G polymorphism and susceptibility to cancer under five genetic models (all P < 0.05). Ethnicity subgroup analysis implied that significant difference was detected for rs2252070 A>G polymorphism with increased risk of cancers among Asians and Caucasians in majority of the groups. Our findings suggest significant association for MMP-13 rs2252070 A>G to increased susceptibility to human cancer, especially in the progression of lung carcinoma.

Wang X, Cao X
Regulation of metastasis of pediatric multiple myeloma by MMP13.
Tumour Biol. 2014; 35(9):8715-20 [PubMed] Related Publications
The molecular mechanism underlying metastasis of pediatric multiple myeloma (MM) remains elusive. Here, we showed that the levels of MMP13 are significantly higher in MM from young patients than those from adult patients. Moreover, a strong correlation of the MMP13 and phosphorylated fibroblast growth factor receptor 4 (FGFR4) levels was detected in MM from young patients. To prove a causal link between activation of fibroblast growth factor receptors (FGFR) signaling pathway and MMP13 expression, we used a human MM line, RPMI-8226 (8226), to study the underlying molecular basis. We found that FGF1-induced FGFR4 phosphorylation in 8,226 cells resulted in significant activation of MMP13, and consequently, an increase in cancer invasiveness. FGFR4 inhibition in 8,226 cells abolished FGF1-stimulated MMP13 expression, suggesting that activation of FGFR signaling pathway in MM may promote cancer metastasis by inducing MMP13 expression. To define the signaling cascades downstream of FGFR4 activation for MMP13 activation, we applied specific inhibitors for PI3K, Jun N-terminal kinase (JNK), and ERK/MAPK, respectively, to the FGF1-stimulated 8,226 cells. We found that only inhibition of ERK1/2 significantly decreased the activation of MMP13 in response to FGF stimulation, suggesting that activation of FGFR signaling may activate ERK/MAPK, rather than JNK or PI3K pathway to activate MMP13 expression in 8,226 cells. Our study thus highlights FGFR4 signaling pathway and MMP13 as novel therapeutic targets for MM.

Ye Z, Jingzhong L, Yangbo L, et al.
Propofol inhibits proliferation and invasion of osteosarcoma cells by regulation of microRNA-143 expression.
Oncol Res. 2013; 21(4):201-7 [PubMed] Related Publications
Propofol is one of the extensively commonly used intravenous anesthetic agents. Previous studies have indicated that propofol has the ability to influence the biological behavior of several human cancer cells. However, the effect of propofol on osteosarcoma and its related molecular mechanisms are still not clear. Here we found that propofol significantly elevated the expression of miR-143, inhibited cell proliferation and invasion, and promoted apoptosis in osteosarcoma cell line MG63. Propofol also efficiently decreased protein expression of matrix metalloproteinase 13 (MMP-13). Moreover, the overexpression of miR-143 decreased MMP-13 protein level. Finally, the neutralization of miR-143 by anti-miR-143 antibody reversed the effect of propofol on cell proliferation, apoptosis, and invasion and upregulated MMP-13 expression in MG63 cells. Taken together, propofol may have antitumor potential in osteosarcoma, which is partly due to the downregulation of MMP-13 expression by miR-143.

Yan F, Yu Y, Chow DC, et al.
Identification of verrucarin a as a potent and selective steroid receptor coactivator-3 small molecule inhibitor.
PLoS One. 2014; 9(4):e95243 [PubMed] Free Access to Full Article Related Publications
Members of the steroid receptor coactivator (SRC) family are overexpressed in numerous types of cancers. In particular, steroid receptor coactivator 3 (SRC-3) has been recognized as a critical coactivator associated with tumor initiation, progression, recurrence, metastasis, and chemoresistance where it interacts with multiple nuclear receptors and other transcription factors to enhance their transcriptional activities and facilitate cross-talk between pathways that stimulate cancer progression. Because of its central role as an integrator of growth signaling pathways, development of small molecule inhibitors (SMIs) against SRCs have the potential to simultaneously disrupt multiple signal transduction networks and transcription factors involved in tumor progression. Here, high-throughput screening was performed to identify compounds able to inhibit the intrinsic transcriptional activities of the three members of the SRC family. Verrucarin A was identified as a SMI that can selectively promote the degradation of the SRC-3 protein, while affecting SRC-1 and SRC-2 to a lesser extent and having no impact on CARM-1 and p300 protein levels. Verrucarin A was cytotoxic toward multiple types of cancer cells at low nanomolar concentrations, but not toward normal liver cells. Moreover, verrucarin A was able to inhibit expression of the SRC-3 target genes MMP2 and MMP13 and attenuated cancer cell migration. We found that verrucarin A effectively sensitized cancer cells to treatment with other anti-cancer drugs. Binding studies revealed that verrucarin A does not bind directly to SRC-3, suggesting that it inhibits SRC-3 through its interaction with an upstream effector. In conclusion, unlike other SRC SMIs characterized by our laboratory that directly bind to SRCs, verrucarin A is a potent and selective SMI that blocks SRC-3 function through an indirect mechanism.

de la Peña S, Sampieri CL, Ochoa-Lara M, et al.
Expression of the matrix metalloproteases 2, 14, 24, and 25 and tissue inhibitor 3 as potential molecular markers in advanced human gastric cancer.
Dis Markers. 2014; 2014:285906 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: During progression of gastric cancer (GC), degradation of the extracellular matrix is mediated by the matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs): changes in the expression of these have been related to unfavorable prognosis in GC.
OBJECTIVE: To analyze the expression of certain MMPs and TIMPs in chronic superficial gastritis (SG) and GC.
METHODS: The expression of MMPs and TIMPs was determined using qRT-PCR; the expression was classified, using threshold cycle (C(T)) values, as very high (C(T) ≤ 25), high (C(T) = 26-30), moderate (C(T) = 31-35), low (C(T) = 36-39), or not detected (C(T) = 40). Strength of association was estimated between the proteins, which were detected by Western blot, and the risk of developing GC.
RESULTS: We found a high expression of MMP1, MMP2, MMP14, TIMP1, and TIMP3; moderate one of MMP9 and MMP25, and low one of MMP13 and MMP24 in both tissues. In absolute mRNA levels, significant differences were found in expression of MMP2, MMP24, and MMP25, which are overexpressed in GC compared with SG. The presence of the proteins MMP-14 and TIMP-3 was associated with the risk of developing GC.
CONCLUSIONS: We consider that MMP2, MMP24, and MMP25 and the proteins MMP-14 and TIMP-3 could be candidates for prognostic molecular markers in GC.

Celardo I, Antonov A, Amelio I, et al.
p63 transcriptionally regulates the expression of matrix metallopeptidase 13.
Oncotarget. 2014; 5(5):1279-89 [PubMed] Free Access to Full Article Related Publications
p63 is a transcriptional factor belonging to p53 family of genes. Beside the role in cancer, partially shared with p53 and the other member p73, p63 also plays exclusive roles in development and homeostasis of ectodermal/epidermal-related organs. Here we show that p63 transcriptionally controls the expression of the matrix metallopeptidase 13 (MMP13). p63 binds a p53-like responsive element in the human promoter of MMP13, thus promoting the activation of its transcription. The catalytic activity of MMP13 is required in high invasion capacity of metastatic cancer cells, however, although p63 and MMP13 expression correlates in cancer patients, their co-expression does not predict cancer patient survival. Our results demonstrate that p63 directly controls MMP13 expression.

Boregowda RK, Olabisi OO, Abushahba W, et al.
RUNX2 is overexpressed in melanoma cells and mediates their migration and invasion.
Cancer Lett. 2014; 348(1-2):61-70 [PubMed] Article available free on PMC after 28/06/2015 Related Publications
In the present study, we investigated the role of the transcription factor RUNX2 in melanomagenesis. We demonstrated that the expression of transcriptionally active RUNX2 was increased in melanoma cell lines as compared with human melanocytes. Using a melanoma tissue microarray, we showed that RUNX2 levels were higher in melanoma cells as compared with nevic melanocytes. RUNX2 knockdown in melanoma cell lines significantly decreased Focal Adhesion Kinase expression, and inhibited their cell growth, migration and invasion ability. Finally, the pro-hormone cholecalciferol reduced RUNX2 transcriptional activity and decreased migration of melanoma cells, further suggesting a role of RUNX2 in melanoma cell migration.

Moreno-Ortiz JM, Gutiérrez-Angulo M, Partida-Pérez M, et al.
Association of MMP7-181A/G and MMP13-77A/G polymorphisms with colorectal cancer in a Mexican population.
Genet Mol Res. 2014; 13(2):3537-44 [PubMed] Related Publications
Colorectal cancer (CRC) is characterized by enhanced expression and activity of several metalloproteinases (MMPs), including MMP13 and MMP7, which play an important role in tumor invasion and metastasis. The objective of this study was to analyze the association of functional MMP7-181A/G and MMP13-77A/G promoter polymorphisms with susceptibility to CRC in a Mexican population. Genomic DNA samples were obtained from peripheral blood of 102 CRC patients and 125 blood donors who were included as the control group. Identification of polymorphisms was based on polymerase chain reaction-restriction fragment length polymorphism methodology. The association was estimated by the odds ratio (OR) test. The results showed that MMP7-181A/G and MMP13-77A/G variants were associated with CRC. For MMP7-181A/G, the AA (P=0.02, OR=3.38, 95% confidence interval (CI)=1.16-9.84) and AG (P=0.01, OR=3.4, 95%CI=1.17-9.83) genotypes were associated with an increased risk of CRC. For MMP13-77A/G, the AA and AG genotypes were associated with CRC (AA genotype: P=0.04, OR=3.2, 95%CI=1.004-10.2; AG genotype: P=0.01, OR=4.08, 95%CI=1.3-13.07). In conclusion, AA and AG genotype carriers for both polymorphisms are at a higher risk of developing CRC in this Mexican population.

Wu X, Zeng Z, Xu L, et al.
Increased expression of IL17A in human gastric cancer and its potential roles in gastric carcinogenesis.
Tumour Biol. 2014; 35(6):5347-56 [PubMed] Related Publications
Inflammatory cytokines modulate immune responses in the tumor microenvironment during progression. The role of interleukin (IL) 17A in cancer is currently under debate. We aim to investigate the expression of IL17A in situ tumors as well as in nontumor gastric mucosa tissues and further explore the functional significance of IL17A on gastric cancer cells in vitro. We found that compared with nontumor regions, the expression of IL17A were increased significantly in tumors of gastric cancer patients (P=0.007). The immunoreactivity for IL17A was found only in cytoplasm of inflammatory cells as well as vascular endothelial cells but not in tumor cells. Consistently, IL17A transcription was silenced in a variety of gastric cancer cell lines. In vitro, recombinant human IL17A protein promotes cell proliferation and monolayer wound healing of both AGS and SGC7901cells, in a dose-dependent manner. Besides, IL17A inhibits H2O2-induced cell apoptosis. Expression of IL6 and MMP13 mRNA was increased significantly after IL17A stimulation. These data suggest that accumulation of intratumoral IL17A-producing cells may promote gastric cancer progression directly or by inducing key signal transduction pathways implicated in gastric carcinogenesis.

Yang G, Ma F, Zhong M, et al.
Interleukin-11 induces the expression of matrix metalloproteinase 13 in gastric cancer SCH cells partly via the PI3K-AKT and JAK-STAT3 pathways.
Mol Med Rep. 2014; 9(4):1371-5 [PubMed] Related Publications
Interleukin (IL)-11 is expressed in the majority of gastric carcinomas and has been associated with an aggressive phenotype and poor prognosis of gastric adenocarcinoma. Matrix metalloproteinase (MMP)-13 has been detected in numerous invasive malignant tumor types and exhibits a broad spectrum of activities on connective tissue components. In this study, we investigated whether IL-11 affects the expression of MMP-13 in human gastric cancer cells, as well as the underlying mechanism. Using western blot assays, we investigated the effect of recombinant human (rh) IL-11 on the expression of MMP-13 in gastric carcinoma cell lines. Using the PI3K inhibitor wortmannin and RNA interference to target the STAT3 gene, we investigated the effects of PI3K inhibition and/or STAT3 depletion on the expression of the MMP-13 protein. Results showed that IL-11 induced MMP-13 expression in a time- and concentration-dependent manner in SCH cells. IL-11 activated PI3K-AKT and JAK-STAT3 signal transduction. Wortmannin and depletion of STAT3 by means of small interfering RNA (siRNA) synergistically reduced the expression of MMP-13. These findings suggested that IL-11 induces the expression of MMP-13 in gastric cancer SCH cells partly via the PI3K-AKT and JAK-STAT3 pathways.

Silva SD, Alaoui-Jamali MA, Hier M, et al.
Cooverexpression of ERBB1 and ERBB4 receptors predicts poor clinical outcome in pN+ oral squamous cell carcinoma with extranodal spread.
Clin Exp Metastasis. 2014; 31(3):307-16 [PubMed] Related Publications
Overexpression of members of the ErbB receptor family is common in oral squamous cell carcinomas (OSCC); however, their prognostic value for aggressive OSCC has been debated. Extranodal spread to cervical lymph nodes is the most significant prognostic indicator in OSCC. In the present study, we investigated the clinical significance of single versus paired overexpression of members of the ErbB receptor family in 82 OSCC patients with lymph nodes metastasis, with or without capsular rupture (CR) followed by at least 10 years. Immunohistochemistry analysis revealed a common overexpression of ErbB1 (P = 0.021), ErbB2 (P = 0.001), ErbB4 (P = 0.048), as well as MMP-2 (P = 0.043) in OSCC cases with CR+. Increased expression of ErbB1 was associated with MMP-2 in tumors with advanced clinical stages, including poorly differentiated (grade III) tumors (P < 0.050). Vascular embolization was associated with MMP-2 (P = 0.021) and MMP-13 (P = 0.010) overexpression. Survival analysis revealed a lower survival probability in tumors overexpressing ErbB1 (P = 0.038), ErbB4 (P = 0.043), and MMP-12 (P = 0.050). As well a strong association was observed in cases with high risk of recurrence and strong immunostaining for ErbB1 (P = 0.017), ErbB4 (P = 0.008), MMP-1 (P = 0.003), MMP-2 (P = 0.016), MMP-10 (P = 0.041), and MMP-13 (P = 0.005). Stratified multivariate survival analysis revealed a strong prognostic interdependence of ErbB1 and ErbB4 cooverexpression in predicting the worst overall and disease-free survivals (P = 0.0013 and P = 0.0004, respectively). Taken together, these results support a cooperation of ErbB1, ErbB4, and members of the MMP family in predicting OSCC invasion and poor clinical outcomes.

Zeng L, Wang W, Rong XF, et al.
Chondroprotective effects and multi-target mechanisms of Icariin in IL-1 beta-induced human SW 1353 chondrosarcoma cells and a rat osteoarthritis model.
Int Immunopharmacol. 2014; 18(1):175-81 [PubMed] Related Publications
Cartilage degradation is the most predominant pathological change during osteoarthritis (OA). Furthermore, accumulating evidence suggests that an excess of matrix metalloproteinase-13 (MMP-13) plays a critical role in the breakdown of cartilage. Here, the effects of Icariin on the expression of MMP-13 in IL-1β-induced SW 1353 chondrosarcoma cells were investigated. In addition, the in vivo effects of Icariin on an experimental rat model of OA induced by anterior cruciate ligament transection (ACLT) was examined. SW1353 chondrosarcoma cells were pretreated with or without Icariin and MAPK and Wnt/β-catenin signaling pathway inhibitors, then were stimulated with IL-1β. In rats, experimental OA was induced by ACLT. These rats then received intra-articular injections of vehicle, signaling pathway inhibitors, and/or Icariin. Expression of MMP-13, phosphorylated p38, phosphorylated JNK, and β-catenin were verified by western blotting. In addition, levels of MMP-13 mRNA were detected using quantitative real-time PCR. In histological analyses, treatment with Icariin reduced the number of cartilage lesions present. In addition, treatment with Icariin was associated with lower levels of phosphorylated p38, phosphorylated JNK, and β-catenin in both IL-1β-induced SW1353 chondrosarcoma cells and in the rat OA model. Furthermore, the suppressive effect of Icariin on MMP-13 was greater than that exhibited by other signaling pathway inhibitors. Overall, these data suggest that Icariin has therapeutic potential for the treatment of OA.

Li H, Huang F, Fan L, et al.
Phosphatidylethanolamine-binding protein 4 is associated with breast cancer metastasis through Src-mediated Akt tyrosine phosphorylation.
Oncogene. 2014; 33(37):4589-98 [PubMed] Related Publications
Metastasis is responsible for more than 90% of the mortality observed among patients with breast cancer. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of the PEBP family and functions as an anti-apoptotic molecule. Here, we found that the metastatic MDA-MB-231 breast cancer cells expressed much higher levels of hPEBP4 than the nonmetastatic MCF-7 breast cancer cells and that the expression levels of hPEBP4 were positively correlated with the metastasis of clinical breast cancer. The hPEBP4 overexpression in the MDA-MB-231 cells significantly promoted cell invasion in vitro and increased the development of lymph node metastasis in vivo. Conversely, the silencing of hPEBP4 suppressed the cell-invasive ability both in vitro and in vivo. Further investigation showed that hPEBP4 promoted the expression or activity of the metastasis-related proteinases MMP (matrix metalloproteinase) 2, MMP9 and MMP13. This hPEBP4-potentiated cell invasion and MMP expression is due to an increase in Akt activation. Knockdown of Akt restored hPEBP4-induced breast tumor metastasis in the hPEBP4-MDA-MB-231 xenograft mouse model. Moreover, we found that hPEBP4 functioned as a scaffolding molecule and enhanced the association of Akt with Src to promote Akt tyrosine phosphorylation, a prerequisite for the full activation of Akt, in a phosphatidylethanolamine-binding domain-dependent manner. Given the present information about human breast cancer, these functional data from cell culture and animal studies suggest that, in human breast cancer hPEBP4 is a novel and clinically relevant metastasis accelerator gene and may be a new diagnostic marker and therapeutic target for breast cancer metastasis.

Haas DA, Bala K, Büsche G, et al.
The inflammatory kinase MAP4K4 promotes reactivation of Kaposi's sarcoma herpesvirus and enhances the invasiveness of infected endothelial cells.
PLoS Pathog. 2013; 9(11):e1003737 [PubMed] Article available free on PMC after 28/06/2015 Related Publications
Kaposi's sarcoma (KS) is a mesenchymal tumour, which is caused by Kaposi's sarcoma herpesvirus (KSHV) and develops under inflammatory conditions. KSHV-infected endothelial spindle cells, the neoplastic cells in KS, show increased invasiveness, attributed to the elevated expression of metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). The majority of these spindle cells harbour latent KSHV genomes, while a minority undergoes lytic reactivation with subsequent production of new virions and viral or cellular chemo- and cytokines, which may promote tumour invasion and dissemination. In order to better understand KSHV pathogenesis, we investigated cellular mechanisms underlying the lytic reactivation of KSHV. Using a combination of small molecule library screening and siRNA silencing we found a STE20 kinase family member, MAP4K4, to be involved in KSHV reactivation from latency and to contribute to the invasive phenotype of KSHV-infected endothelial cells by regulating COX-2, MMP-7, and MMP-13 expression. This kinase is also highly expressed in KS spindle cells in vivo. These findings suggest that MAP4K4, a known mediator of inflammation, is involved in KS aetiology by regulating KSHV lytic reactivation, expression of MMPs and COX-2, and, thereby modulating invasiveness of KSHV-infected endothelial cells.

Chiang KC, Chen SC, Yeh CN, et al.
MART-10, a less calcemic vitamin D analog, is more potent than 1α,25-dihydroxyvitamin D3 in inhibiting the metastatic potential of MCF-7 breast cancer cells in vitro.
J Steroid Biochem Mol Biol. 2014; 139:54-60 [PubMed] Related Publications
With the recent advance in breast cancer therapy, the survival rate of breast cancer patients has improved greatly. In spite of the progress, 25-50% of breast cancer patients eventually will develop metastasis. Due to limited early detection methods, metastasis is usually diagnosed at the late stages beyond recovery likely due to resistance to currently available breast cancer therapies. Thus, a new strategy to prevent cancer cell growth and repress tumor metastasis is desirable. The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], has anti-invasion and anti-migration properties in pre-clinical studies, yet its clinical application has been hampered by its hypercalcemic side effect. Previously, we have demonstrated that a new class of less-calcemic vitamin D analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), is 1000-fold more active than 1α,25(OH)2D3 in suppressing MCF-7 cells growth through cell cycle arrest and apoptosis induction. In the current study, we show for the first time that MART-10 is more active than 1α,25(OH)2D3 in preventing MCF-7 cell invasion and migration likely mediated through the upregulation of E-cadherin, and the downregulation of Snail, Slug, and Twist, the transcription factors implicated in epithelial-mesenchymal transition (EMT), as well as MMP-13. Based on the current in vitro and the highly anti-tumor characteristics of MART-10 in a pancreatic xenograft model, MART-10 is deemed as a promising candidate for breast cancer treatment. Further in vivo animal study comparing MART-10 with 1α,25(OH)2D3 and other potent and less calcemic analogs of vitamin D is warranted.

Passariello A, De Brasi D, Defferrari R, et al.
Constitutional 11q14-q22 chromosome deletion syndrome in a child with neuroblastoma MYCN single copy.
Eur J Med Genet. 2013; 56(11):626-34 [PubMed] Related Publications
Constitutional 11q deletion is a chromosome imbalance possibly found in MCA/MR patients analyzed for chromosomal anomalies. Its role in determining the phenotype depends on extension and position of deleted region. Loss of heterozygosity of 11q (region 11q23) is also associated with neuroblastoma, the most frequent extra cranial cancer in children. It represents one of the most frequent cytogenetic abnormalities observed in the tumor of patients with high-risk disease even if germline deletion of 11q in neuroblastoma is rare. Hereby, we describe a 18 months old girl presenting with trigonocephaly and dysmorphic facial features, including hypotelorism, broad depressed nasal bridge, micrognathia, synophrys, epicanthal folds, and with a stage 4 neuroblastoma without MYCN amplification, carrying a germline 11q deletion (11q14.1-q22.3), outside from Jacobsen syndrome and from neuroblastoma 11q critical regions. The role of 11q deletion in determining the clinical phenotype and its association with neuroblastoma development in the patient are discussed.

Tan MY, Mu XY, Liu B, et al.
SUMO-specific protease 2 suppresses cell migration and invasion through inhibiting the expression of MMP13 in bladder cancer cells.
Cell Physiol Biochem. 2013; 32(3):542-8 [PubMed] Related Publications
BACKGROUND: SUMO-specific protease 2 (SENP2) is a de-SUMOylation protease family member which has an indispensable role in the regulation of NF-κB transcriptional activation and Wnt signaling. However, whether SENP2 plays a role in tumor metastasis is completely unknown.
METHODS: Real-time PCR and Western blot was used to detect the expression of SENP2 in human bladder cancer samples and cell lines. Small interfering RNA (siRNA) was used to silencing the expression of SENP2. Matrigel-coated invasion chambers were used to detect the invasion ability of SENP2 in bladder cancer cells.
RESULTS: SENP2 was down-regulated in bladder cancer samples. SENP2 inhibited bladder cancer cells migration and invasion in vitro. Transcriptional analysis of several genes associated with tumor metastasis and invasion demonstrated that SENP2 selectively down-regulated MMP13 in bladder cancer cells. Further analysis indicated that silencing of MMP13 rescued the invasive phenotype in SENP2 expressing T24 cells.
CONCLUSION: SENP2 functions as a tumor metastasis suppressor in bladder cancer. The effects of SENP2 on bladder cancer invasion are partially mediated by inhibiting the expression of MMP13.

VAN Nguyen S, Skarstedt M, Löfgren S, et al.
Gene polymorphism of matrix metalloproteinase-12 and -13 and association with colorectal cancer in Swedish patients.
Anticancer Res. 2013; 33(8):3247-50 [PubMed] Related Publications
BACKGROUND: It has been widely reported that matrix metalloproteinases (MMPs) have fundamental roles in pathological processes in cancer through degradation of basal membranes and extracellular matrix. For MMP12 and MMP13, a functional single nucleotide polymorphism (SNP) has been detected -82A →G (rs2276109) and -77A →G (rs2252070), respectively. These SNPs are suggested to have an influence on different diseases. The present study evaluated the association between these SNPs in patients with colorectal cancer (CRC) patients and healthy controls.
PATIENTS AND METHODS: Using the TaqMan system, these SNPs were screened in 385 patients with CRC and 619 controls.
RESULTS: No significant difference in genotype distribution or in allelic frequencies was found between the two groups. However, we showed that the AA MMP-12 genotype is connected with a higher risk of disseminated CRC (Odds Ratio=1.77; 95% Confidence Interval=1.11-2.81, p=0.018).
CONCLUSION: The results of this study suggest that the -82A →G (rs2276109) polymorphism of the MMP12 gene reflects clinical outcome of patients with CRC.

Dorjgochoo T, Zheng Y, Gao YT, et al.
No association between genetic variants in angiogenesis and inflammation pathway genes and breast cancer survival among Chinese women.
Cancer Epidemiol. 2013; 37(5):619-24 [PubMed] Article available free on PMC after 28/06/2015 Related Publications
BACKGROUND: Angiogenesis and inflammation are implicated in breast cancer prognosis; however, the role of individual germline variation in related genes is unknown.
METHODS: A two-stage candidate pathway association study was conducted among 6983 Chinese women. Stage 1 included 2884 women followed for a median of 5.7 years; Stage 2 included 4099 women followed for a median of 4.0 years. Cox proportional hazards regression was used to estimate the effects of genetic variants on disease-free survival (DFS) and overall survival (OS).
RESULTS: Stage 1 included genotyping of 506 variants in 22 genes; analysis was conducted for 370 common variants. Nominally significant associations with DFS and/or OS were found for 20 loci in ten genes in Stage 1; variants in 19 loci were successfully genotyped and evaluated in Stage 2. In analyses of both study stages combined, nominally significant associations were found for nine variants in seven genes; none of these associations surpassed a significance threshold level corrected for the total number of variants evaluated in this study.
CONCLUSIONS: No association with survival was found for 370 common variants in 22 angiogenesis and inflammation pathway genes among Chinese women with breast cancer.
IMPACT: Our data do not support a large role for common genetic variation in 22 genes in breast cancer prognosis; research on angiogenesis and inflammation genes should focus on common variation in other genes, rare host variants, or tumor alterations.

Murakami Y, Watari K, Shibata T, et al.
N-myc downstream-regulated gene 1 promotes tumor inflammatory angiogenesis through JNK activation and autocrine loop of interleukin-1α by human gastric cancer cells.
J Biol Chem. 2013; 288(35):25025-37 [PubMed] Article available free on PMC after 28/06/2015 Related Publications
The expression of N-myc downstream-regulated gene 1 (NDRG1) was significantly correlated with tumor angiogenesis and malignant progression together with poor prognosis in gastric cancer. However, the underlying mechanism for the role of NDRG1 in the malignant progression of gastric cancer remains unknown. Here we examined whether and how NDRG1 could modulate tumor angiogenesis by human gastric cancer cells. We established NU/Cap12 and NU/Cap32 cells overexpressing NDRG1 in NUGC-3 cells, which show lower tumor angiogenesis in vivo. Compared with parental NU/Mock3, NU/Cap12, and NU/Cap32 cells: 1) induced higher tumor angiogenesis than NU/Mock3 cells accompanied by infiltration of tumor-associated macrophages in mouse dorsal air sac assay and Matrigel plug assay; 2) showed much higher expression of CXC chemokines, MMP-1, and the potent angiogenic factor VEGF-A; 3) increased the expression of the representative inflammatory cytokine, IL-1α; 4) augmented JNK phosphorylation and nuclear expression of activator protein 1 (AP-1). Further analysis demonstrated that knockdown of AP-1 (Jun and/or Fos) resulted in down-regulation of the expression of VEGF-A, CXC chemokines, and MMP-1, and also suppressed expression of IL-1α in NDRG1-overexpressing cell lines. Treatment with IL-1 receptor antagonist (IL-1ra) resulted in down-regulation of JNK and c-Jun phosphorylation, and the expression of VEGF-A, CXC chemokines, and MMP-1 in NU/Cap12 and NU/Cap32 cells. Finally, administration of IL-1ra suppressed both tumor angiogenesis and infiltration of macrophages by NU/Cap12 in vivo. Together, activation of JNK/AP-1 thus seems to promote tumor angiogenesis in relationship to NDRG1-induced inflammatory stimuli by gastric cancer cells.

Yang J, Du X
Genomic and molecular aberrations in malignant peripheral nerve sheath tumor and their roles in personalized target therapy.
Surg Oncol. 2013; 22(3):e53-7 [PubMed] Related Publications
Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors with a high rate of local recurrence and a significant tendency to metastasize. Its dismal outcome points to the urgent need to establish better therapeutic strategies for patients harboring MPNSTs. The investigations of genomic and molecular aberrations in MPNSTs which detect many chromosomal aberrations, pathway abnormalities, and specific molecular aberrant events would supply multiple potential therapy targets and contribute to achievement of personalized medicine. The involved genes in the significant gains aberrations include BIRC5, CCNE2, DAB2, DDX15, EGFR, DAB2, MSH2, CDK6, HGF, ITGB4, KCNK12, LAMA3, LOXL2, MET, and PDGFRA. The involved genes in the significant deletion aberrations include CDH1, GLTSCR2, EGR1, CTSB, GATA3, SULT2A1, GLTSCR2, HMMR/RHAMM, LICAM2, MMP13, p16/INK4a, RASSF2, NM-23H1, and TP53. These genetic aberrations involve in several important signaling pathways such as TFF, EGFR, ARF, IGF1R signaling pathways. The genomic and molecular aberrations of EGFR, IGF1R, SOX9, EYA4, TOP2A, ETV4, and BIRC5 exhibit great promise as personalized therapeutic targets for MPNST patients.

Halder SK, Osteen KG, Al-Hendy A
Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and -9 in human uterine fibroid cells.
Hum Reprod. 2013; 28(9):2407-16 [PubMed] Article available free on PMC after 28/06/2015 Related Publications
STUDY QUESTION: Can biologically active vitamin D3 [1,25(OH)₂D3] regulate the expression and activity of matrix metalloproteinases (MMPs) in human uterine fibroid cells?
SUMMARY ANSWER: 1,25(OH)₂D3 effectively reduced the expression and activities of MMP-2 and MMP-9 in cultured human uterine fibroid cells.
WHAT IS KNOWN ALREADY: Uterine fibroids (leiomyoma) express higher levels of MMP activity than adjacent normal myometrium, and this is associated with uterine fibroid pathogenesis. However, it is unknown whether 1,25(OH)₂D3 can regulate the expression and activities of MMPs in human uterine fibroid cells.
STUDY DESIGN, SIZE, DURATION: Surgically removed fresh fibroid tissue was used to generate primary uterine fibroid cells.
PARTICIPANTS/MATERIALS, SETTING, METHODS: An immortalized human uterine fibroid cell line (HuLM) and/or primary human uterine fibroid cells isolated from fresh fibroid tissue were used to examine the expression of several MMPs, tissue inhibitors of metalloproteinases (TIMP) 1 and 2 and the activities of MMP-2 and MMP-9 after 1,25(OH)₂D3 treatment. Real-time PCR and western blots analyses were used to measure mRNA and protein expression of MMPs, respectively. Supernatant cell culture media were analyzed for MMP-2 and MMP-9 activities using a gelatin zymography assay.
MAIN RESULTS AND THE ROLE OF CHANCE: 1-1000 nM 1,25(OH)₂D3 significantly reduced mRNA levels of MMP-2 and MMP-9 in HuLM cells in a concentration-dependent manner (P < 0.5 to P < 0.001). The mRNA levels of MMP-1, MMP-3, MMP-13 and MMP-14 in HuLM cells were also reduced by 1,25(OH)₂D3. 1,25(OH)₂D3 significantly reduced MMP-2 and MMP-9 protein levels in a concentration-dependent manner in both HuLM and primary uterine fibroid cells (P < 0.05 to P < 0.001). Moreover, 1,25(OH)₂D3 increased the mRNA levels of vitamin D receptor (VDR) and TIMP-2 in a concentration-dependent manner in HuLM cells (P < 0.05 to P < 0.01). 1,25(OH)₂D3 also significantly increased protein levels of VDR and TIMP-2 in all cell types tested (P < 0.05 to P < 0.001). Gelatin zymography revealed that pro-MMP-2, active MMP-2 and pro-MMP-9 were down-regulated by 1,25(OH)₂D3 in a concentration-dependent manner; however, the active MMP-9 was undetectable.
LIMITATIONS, REASONS FOR CAUTION: This study was performed using in vitro uterine fibroid cell cultures and the results were extrapolated to in vivo situation of uterine fibroids. Moreover, in this study the interaction of vitamin D3 with other regulators such as steroid hormone receptors was not explored.
WIDER IMPLICATIONS OF THE FINDINGS: This study reveals an important biological function of 1,25(OH)₂D3 in the regulation of expression and activities of MMP-2 and MMP-9. Thus, 1,25(OH)₂D3 might be a potential effective, safe non-surgical treatment option for human uterine fibroids.

Yang Z, Zhang Y, Wang L
A feedback inhibition between miRNA-127 and TGFβ/c-Jun cascade in HCC cell migration via MMP13.
PLoS One. 2013; 8(6):e65256 [PubMed] Article available free on PMC after 28/06/2015 Related Publications
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is increasing in frequency in the U.S. The major reason for the low postoperative survival rate of HCC is widespread intrahepatic metastasis or invasion, and activation of TGFβ signaling is associated with the invasive phenotype. This study aims at determining the novel function of miR-127 in modulating HCC migration. Overexpression of miR-127 inhibits HCC cell migration, invasion and tumor growth in nude mice. MiR-127 directly represses matrix metalloproteinase 13 (MMP13) 3'UTR activity and protein expression, and diminishes MMP13/TGFβ-induced HCC migration. In turn, TGFβ decreases miR-127 expression by enhancing c-Jun-mediated inhibition of miR-127 promoter activity. In contrast, p53 transactivates miR-127 promoter and induces miR-127 expression, which is antagonized by c-Jun. The inhibition of miR-127 by c-Jun is through TGFβ-mediated ERK and JNK pathways. The lower miR-127 expression shows a negative correlation with the higher MMP13 expression in a subset of human HCC specimens. This is the first report elucidating a feedback regulation between miR-127 and the TGFβ/c-Jun cascade in HCC migration via MMP13 that involves a crosstalk between the oncogene c-Jun and tumor suppressor p53.

Wu D, Huang P, Wang L, et al.
MicroRNA-143 inhibits cell migration and invasion by targeting matrix metalloproteinase 13 in prostate cancer.
Mol Med Rep. 2013; 8(2):626-30 [PubMed] Related Publications
MicroRN-143 (miR‑143) has been previously reported to be downregulated in specific types of cancer, including colorectal, bladder, oral squamous cell, pituitary, cervical, nasopharyngeal, lymphoma and prostate cancer. In the present study, the effects of miR-143 on prostate cancer cell migration and invasion were examined. Following transfection with miR-143, miR-143 expression, cell migration and invasion assays, luciferase assay and western blot analysis were conducted in prostate cancer cell lines. The results indicated that miR-143 inhibits cell migration and invasion in DU145 and PC-3 cells. In addition, to the best of our knowledge, miR-143 was reported for the first time to directly target matrix metalloproteinase 13 (MMP-13) in prostate cancer. The results of the present study demonstrated that miR-143 suppresses cell migration and invasion by targeting MMP-13 in prostate cancer cell lines. These results indicated that miR-143 may be suitable for the development of novel molecular markers and therapeutic approaches to inhibit metastasis in prostate cancer.

Wang L, Wang Y, Bian H, et al.
Molecular characteristics of homologous salivary adenoid cystic carcinoma cell lines with different lung metastasis ability.
Oncol Rep. 2013; 30(1):207-12 [PubMed] Related Publications
Although the homologous salivary adenoid cystic carcinoma (SACC) cell lines SACC-83 and SACC-LM have already been used as SACC models to investigate the underlying mechanisms of metastasis, the molecular features of these SACC cell lines remain unclear. We screened 136 genes related to metastasis in order to investigate the biological and molecular properties of these two cell lines by short tandem repeat (STR) profiling, immunostaining, transwell invasion assay, real-time PCR and western blotting. STR and immunostaining results showed that SACC-83 and SACC-LM are homologous cancer cell lines, derived from adenoepithelial cells and, to date, are not contaminated by each other or other cancer cell lines. Transwell invasion assay results showed that SACC-LM had increased invasion ability compared to SACC-83. 29 of the 136 differentially expressed genes including EREG, S100P, cyclooxygenase (COX)-2, phospho-Akt (p-Akt), matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-9, MMP-13 and MMP-14 were found following gene screening in SACC-83 and SACC-LM cells. Compared with SACC-83, SACC-LM presents higher expression of COX-2, S100P and lower expression of MMP-2, p-Akt, which could be candidates for identifying the homologous pair cell lines.

Jiang W, Crossman DK, Mitchell EH, et al.
WNT5A inhibits metastasis and alters splicing of Cd44 in breast cancer cells.
PLoS One. 2013; 8(3):e58329 [PubMed] Article available free on PMC after 28/06/2015 Related Publications
Wnt5a is a non-canonical signaling Wnt. Low expression of WNT5A is correlated with poor prognosis in breast cancer patients. The highly invasive breast cancer cell lines, MDA-MB-231 and 4T1, express very low levels of WNT5A. To determine if enhanced expression of WNT5A would affect metastatic behavior, we generated WNT5A expressing cells from the 4T1 and MDA-MB-231 parental cell lines. WNT5A expressing cells demonstrated cobblestone morphology and reduced in vitro migration relative to controls. Cell growth was not altered. Metastasis to the lung via tail vein injection was reduced in the 4T1-WNT5A expressing cells relative to 4T1-vector controls. To determine the mechanism of WNT5A action on metastasis, we performed microarray and whole-transcriptome sequence analysis (RNA-seq) to compare gene expression in 4T1-WNT5A and 4T1-vector cells. Analysis indicated highly significant alterations in expression of genes associated with cellular movement. Down-regulation of a subset of these genes, Mmp13, Nos2, Il1a, Cxcl2, and Lamb3, in WNT5A expressing cells was verified by semi-quantitative RT-PCR. Significant differences in transcript splicing were also detected in cell movement associated genes including Cd44. Cd44 is an adhesion molecule with a complex genome structure. Variable exon usage is associated with metastatic phenotype. Alternative spicing of Cd44 in WNT5A expressing cells was confirmed using RT-PCR. We conclude that WNT5A inhibits metastasis through down-regulation of multiple cell movement pathways by regulating transcript levels and splicing of key genes like Cd44.

Wang JR, Li XH, Gao XJ, et al.
Expression of MMP-13 is associated with invasion and metastasis of papillary thyroid carcinoma.
Eur Rev Med Pharmacol Sci. 2013; 17(4):427-35 [PubMed] Related Publications
BACKGROUND: Collagenase-3 (MMP-13), a matrix metalloproteinase, is a recently identified member of the matrix metalloproteinases (MMPs) with broad substrate specificity, and a potential role in tumor metastasis and invasion has been proposed. Collagenase-3 expression has been reported in many carcinomas. However, the presence and possible implication of MMP-13 in the progression of papillary thyroid carcinomas are unknown.
MATERIALS AND METHODS: In the present study, we examined MMP-13 gene expression in 208 papillary thyroid carcinomas who underwent surgery without preoperative treatment and 100 matched samples of adjacent normal thyroid tissue (Paraffin-embedded tissue samples) by immunohistochemistry analysis. In vitro and in vivo studies were done in order to investigate the effect of MMP-13 overexpression or silencing on cancer cells invasion and metastasis.
RESULTS: We found MMP-13 expression was significantly increased in the tumours from local regional lymph node metastases patients. The MMP-13 was stained more intensely in invading fronts than in central portions of local regional lymph node. No MMP-13 staining was observed in matched samples of adjacent normal thyroid tissue. MMP-13 expression was significantly related with TNM and recurrent disease, no relation was found with age extent of tumour and size of tumour. Studies with cell and mice models indicated that overexpression of MMP-13 increased cell migration and promoted metastasis, and MMP-13 sliencing decreased cell migration.
CONCLUSIONS: The data suggest that MMP-13 is associated with thyroid tumour invasion and metastasis and it may be a potential target for therapeutic intervention.

Sanli M, Akar E, Pehlivan S, et al.
The relationship of metalloproteinase gene polymorphisms and lung cancer.
J Surg Res. 2013; 183(2):517-23 [PubMed] Related Publications
BACKGROUND: We analyzed the relationship between matrix metalloproteinase (MMP)-2, -7, and -13 gene expression and polymorphisms and disease susceptibility and prognosis in patients who had undergone surgery for non-small-cell lung cancers.
MATERIALS AND METHODS: The study group consisted of 132 patients who had undergone radical surgery for non-small-cell lung cancers. The control group consisted of 80 healthy volunteers. We isolated deoxyribonuclease samples for use in analyzing gene polymorphisms from pathology blocks for the patient group and from blood samples for the control group. We identified MMP gene polymorphisms with polymerase chain reaction and restriction fragment length polymorphisms. Results were compared with those of the control group to evaluate disease susceptibility, correlation with other clinical parameters, and with survival and prognosis by using appropriate statistical methods.
RESULTS: When we compared polymorphisms pertaining to MMP genes in healthy controls and lung tumor DNA, we observed a decrease in the MMP-2 (-735) polymorphism GG genotype and increases in the MMP-13 (A77G) polymorphism AG and GG genotypes (P = 0.008, P = 0.047, and P = 0.047, respectively). For the MMP-7 (-181) polymorphism, the genotype did not differ significantly for disease susceptibility. Median overall survival time was 25.5 mo in the MMP-13 AA/AG genotypes and 9.3 mo in the GG genotype.
CONCLUSIONS: Decreases in the MMP-2 (-735) polymorphism GG genotype and increases in the MMP-13 (A77G) polymorphism AG and GG genotypes increase the risk for lung cancer. Furthermore, the presence of the MMP-13 (A77G) polymorphism GG genotype is an unfavorable prognostic factor.

Al-Ahmadi W, Al-Ghamdi M, Al-Souhibani N, Khabar KS
miR-29a inhibition normalizes HuR over-expression and aberrant AU-rich mRNA stability in invasive cancer.
J Pathol. 2013; 230(1):28-38 [PubMed] Article available free on PMC after 28/06/2015 Related Publications
The activities of RNA-binding proteins are perturbed in several pathological conditions, including cancer. These proteins include tristetraprolin (TTP, ZFP36) and HuR (ELAVL1), which respectively promote the decay or stability of adenylate-uridylate-rich (AU-rich) mRNAs. Here, we demonstrated that increased stabilization and subsequent over-expression of HuR mRNA were coupled to TTP deficiency. These findings were observed in breast cancer cell lines with an invasive phenotype and were further confirmed in ZFP36-knockout mouse fibroblasts. We show that TTP-HuR imbalance correlated with increased expression of AU-rich element (ARE) mRNAs that code for cancer invasion genes. The microRNA miR-29a was abundant in invasive breast cancer cells when compared to non-tumourigenic cell types. When normal breast cells were treated with miR-29a, HuR mRNA and protein expression were up-regulated. MiR-29a recognized a seed target in the TTP 3' UTR and a cell-permeable miR-29a inhibitor increased TTP activity towards HuR 3' UTR. This led to HuR mRNA destabilization and restoration of the aberrant TTP-HuR axis. Subsequently, the cancer invasion factors uPA, MMP-1 and MMP-13, and cell invasiveness, were decreased. The TTP:HuR mRNA ratios were also perturbed in samples from invasive breast cancer patients when compared with normal tissues, and were associated with invasion gene expression. This study demonstrates that an aberrant ARE-mediated pathway in invasive cancer can be normalized by targeting the aberrant and functionally coupled TTP-HuR axis, indicating a potential therapeutic approach.

Pande S, Browne G, Padmanabhan S, et al.
Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells.
J Cell Physiol. 2013; 228(8):1784-92 [PubMed] Article available free on PMC after 28/06/2015 Related Publications
The serine/threonine kinase Akt/PKB promotes cancer cell growth and invasion through several downstream targets. Identification of novel substrates may provide new avenues for therapeutic intervention. Our study shows that Akt phosphorylates the cancer-related transcription factor Runx2 resulting in stimulated DNA binding of the purified recombinant protein in vitro. Pharmacological inhibition of the PI3K/Akt pathway in breast cancer cells reduces DNA-binding activity of Runx2 with concomitant reduction in the expression of metastasis-related Runx2 target genes. Akt phosphorylates Runx2 at three critical residues within the runt DNA-binding domain to enhance its in vivo genomic interactions with a target gene promoter, MMP13. Mutation of these three phosphorylation sites reduces Runx2 DNA-binding activity. However, Akt signaling does not appear to interefere with CBFβ-Runx2 interactions. Consequently, expression of multiple metastasis-related genes is decreased and Runx2-mediated cell invasion is supressed. Thus, our work identifies Runx2 as a novel and important downstream mediator of the PI3K/Akt pathway that is linked to metastatic properties of breast cancer cells.

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