TIMP3

Gene Summary

Gene:TIMP3; TIMP metallopeptidase inhibitor 3
Aliases: SFD, K222, K222TA2, HSMRK222
Location:22q12.3
Summary:This gene belongs to the TIMP gene family. The proteins encoded by this gene family are inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix (ECM). Expression of this gene is induced in response to mitogenic stimulation and this netrin domain-containing protein is localized to the ECM. Mutations in this gene have been associated with the autosomal dominant disorder Sorsby's fundus dystrophy. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:metalloproteinase inhibitor 3
Source:NCBIAccessed: 13 March, 2017

Ontology:

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 13 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (9)

Latest Publications: TIMP3 (cancer-related)

Juodzbalys G, Kasradze D, Cicciù M, et al.
Modern molecular biomarkers of head and neck cancer. Part I. Epigenetic diagnostics and prognostics: Systematic review.
Cancer Biomark. 2016; 17(4):487-502 [PubMed] Related Publications
INTRODUCTION: Nearly half of the head and neck cancer cases are diagnosed in late stages. Traditional screening modalities have many disadvantages. The aim of the present article was to review the scientific literature about novel head and neck cancer diagnostics - epigenetic biomarkers.
EVIDENCE ACQUISITION: A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed database. Authors conducted the search of articles in English language published from 2004 to 2015.
EVIDENCE SYNTHESIS: A total of thirty three relevant studies were included in the review. Fifteen of them concerned DNA methylation alterations, nine evaluation of abundancies in histone expressions and nine miRNA expression changes in HNC.
CONCLUSIONS: Considerable number of epigenetic biomarkers have been identified in both tumor tissue and salivary samples. Genes with best diagnostic effectiveness rates and further studying prospects were: TIMP3, DCC, DAPK, CDH1, CCNA1, AIM1, MGMT, HIC1, PAX1, PAX5, ZIC4, p16, EDNRB, KIF1A, MINT31, CD44, RARβ , ECAD. Individual histone and miRNA alterations tend to be hnc specific. Prognostic values of separate biomarkers are ambiguous. No established standards for molecular assay of head and neck cancer was found in order to elude the paradoxical results and discrepancies in separate trials.

Zhang HZ, Shan CG, Huang AP, Wang JM
Characterization of gene methylation in human papillomavirus associated-head and neck squamous cell carcinoma.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
Head and neck squamous cell carcinoma (HNSCC) has become one of the most common forms of cancer worldwide. Hypermethylation-induced silencing of tumor-associated gene has been proposed as an important cofactor in cancer pathology. This paper aimed to characterize the gene methylation patterns in human papillomavirus (HPV) associated-HNSCC. TIMP3 and APC methylation status in neoplastic (N = 92) and non-neoplastic tissues (N = 92) of HNSCC as well as their association with HPV infection were investigated via methylation-specific PCR assays. Results indicated that methylation level of TIMP3 was markedly higher in HPV-positive tumors as compared with HPV-negative tumors. Both TIMP3 and APC methylation were associated with lymph node metastasis and higher clinical stage of tumors. Patients with methylation at TIMP3 or APC had worse prognoses as compared to those without these alterations. This is the first study that shows a possible linkage between HPV infection and APC methylation. Methylation patterns of tumor-related genes may contribute to different disease prognosis in HNSCC according to the HPV infection status.

Zhou Q, Zheng X, Chen L, et al.
Smad2/3/4 Pathway Contributes to TGF-β-Induced MiRNA-181b Expression to Promote Gastric Cancer Metastasis by Targeting Timp3.
Cell Physiol Biochem. 2016; 39(2):453-66 [PubMed] Related Publications
BACKGROUND/AIMS: Transforming growth factor beta (TGF-β) plays a major role in tumorigenesis. MicroRNA-181b (miRNA-181b) is a multifaceted miRNA that has been implicated in many cellular processes such as cell fate determination and cellular invasion. This study aimed to confirm the relationship of miRNA-181b and the TGF-β-Smad2/3/4 pathway with the induction of the epithelial-to-mesenchymal transition (EMT) in gastric cancer.
METHODS: This study investigated the ability of TGF-β to induce migration by wound healing and transwell invasion assays in human gastric cancer cell lines. miRNA expression was altered using miRNA-181b mimic and inhibitor in the same system. Expression of miRNA-181b, the hypothetical target gene Timp3 and EMT-related markers were analyzed by real-time real-time quantitative RT-PCR. Immunoblotting was used to investigate the levels of phospho-Smad2 and Smad4. Dual-luciferase reporter assays were performed to confirm the direct binding of miRNA-181b to Timp3.
RESULTS: miRNA-181b was significantly upregulated in response to TGF-β treatment in gastric cancer cell lines. Overexpression of miR-181b mimic induced an in vitro EMT-like change to a phenotype similar to that following TGF-β treatment alone and was reversed by miRNA-181b inhibitor. Inhibition of TGF-β-Smad2/3 signaling with SD-208 significantly attenuated the upregulation of miRNA-181b. Knockdown of Smad4 in gastric cancer cells strongly attenuated the upregulation of miRNA-181b. Moreover, miR-181b was found to directly target the 3' untranslated region (3'UTR) of Timp3 mRNA affecting TGF-β-induced EMT.
CONCLUSIONS: Our results elucidate a novel mechanism through which the TGF-β pathway regulates the EMT of gastric cancer cells by increasing the levels of miRNA-181b to target Timp3 via the Smad2/3/4-dependent pathway. These findings provide insights into the cellular and environmental factors regulating EMT, which may guide future studies on therapeutic strategies targeting these cells.

Lima MA, Dos Santos L, Turri JA, et al.
Prognostic Value of ADAMTS Proteases and Their Substrates in Epithelial Ovarian Cancer.
Pathobiology. 2016; 83(6):316-26 [PubMed] Related Publications
BACKGROUND: ADAMTS are metalloproteases with disintegrin and thrombospondin motifs. They are secreted proteases playing a role in biological processes such as inflammation, angiogenesis, and urogenital development. ADAMTS have specific substrates, such as the proteoglycans (PG) versican, aggrecan, and brevican. Despite data indicating a role of ADAMTS in tumor invasion and metastases, effects played by these molecules in cancer progression are still controversial. In ovarian cancer, the importance of ADAMTS gene mutations was recently described and related to chemotherapy outcome.
OBJECTIVE: To analyze protein levels of ADAMTS-1, -4, and -5, and TIMP-3 in human ovarian cancer classified as benign, borderline, or malignant. We also assessed the expression of the ADAMTS substrates aggrecan, brevican, and versican in these neoplasms. Correlations between overall survival and protein expression were performed.
METHODS: Tumors were classified according to the WHO Classification of Tumors of Female Reproductive Organs. Protein and PG expression was studied by immunohistochemistry. Differences in labeling were analyzed by percent measurements of stained areas.
RESULTS: ADAMTS-1, ADAMTS-5, and its tissue inhibitor TIMP-3 are increased in borderline and malignant tumors compared to benign neoplasms. Aggrecan and versican levels were increased in malignant subtypes compared to benign ovarian cancer. Higher ADAMTS-1, TIMP-3, and versican expression was associated with a shorter overall survival.
CONCLUSIONS: Comparison of protease, TIMP-3, and substrate expression showed that in malignant tumors all ADAMTS and TIMP-3 expression levels were significantly raised compared to the substrates studied.

Shen B, Jiang Y, Chen YR, et al.
Expression and inhibitory role of TIMP-3 in hepatocellular carcinoma.
Oncol Rep. 2016; 36(1):494-502 [PubMed] Related Publications
As a member of the tissue inhibitor of metallo-proteinases (TIMP) family, it has been reported that TIMP-3 is involved in human cancer development. However, the function of TIMP-3 in hepatocellular carcinoma (HCC) development is unclear. We aimed to determine the biological role of TIMP-3 in HCC by evaluating the effects of its methylation status and expression on HCC cell function. TIMP-3 expression in HCC tissues was visibly analyzed by immunohistochemistry. Methylation of the TIMP-3 promoter was evaluated by methylation-specific PCR. Effects of TIMP-3 on HCC cell growth, apoptosis, migration, and invasion were examined by transfecting the TIMP-3-expressing plasmid, pCMV6. TIMP-3 was expressed in non-tumorous live tissue, but silenced or downregulated in 60% of HCC cases (P<0.05). Reduced protein expression of TIMP-3 was associated with reduced tumor differentiation (P=0.003) and increased metastatic activity (P=0.005) in HCC cell lines. Promoter methylation contributed to the TIMP-3 inactivation. Overexpression of TIMP-3 in HCC cell lines suppressed cell proliferation, induced apoptosis, and inhibited migration and invasion in vitro. TIMP-3 expression is suppressed by promoter methylation in HCC. This inhibitory protein acts as a functional tumor suppressor by inhibiting HCC cell proliferation, invasion, and migration and by inducing apoptosis and cell cycle arrest at the G2/M phase.

Kunz P, Sähr H, Lehner B, et al.
Elevated ratio of MMP2/MMP9 activity is associated with poor response to chemotherapy in osteosarcoma.
BMC Cancer. 2016; 16:223 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Matrix metalloproteinases (MMPs) are crucially involved in the regulation of multiple stages of cancer progression. Elevated MMP levels have been associated with the development of metastases and poor prognosis in several types of cancer. However, the role of MMPs in osteosarcoma and their prognostic value is still unclear. Available data are conflicting, most likely due to different technical approaches. We hypothesized that in contrast to total mRNA or protein levels frequently analyzed in previous studies the enzymatic activities of MMPs and their inhibitors the tissue inhibitors of matrix metalloproteinases (TIMPs) are closer related to their biological functions. We therefore aimed to evaluate the reliability of different zymography techniques for the quantification of MMP and TIMP activities in osteosarcoma biopsies in order to investigate their distribution, possible regulation and prognostic value.
METHODS: All analyses were done using cryo-conserved osteosarcoma pretreatment biopsies (n = 18). Gene and protein expression of MMPs and TIMPs were analyzed by RT-qPCR and western blot analysis, respectively. Overall MMP activity was analyzed by in situ zymography, individual MMP activities were analyzed by gelatin zymography. Reverse zymography was used to detect and quantify TIMP activities.
RESULTS: Strong overall MMP activities could be detected in osteosarcoma pretreatment biopsies with MMP2 and MMP9 as predominant active MMPs. In contrast to total RNA or protein expression MMP2 and MMP9 activities showed significant quantitative differences between good and poor responders. While MMP9 activity was high in the good responder group and significantly decreased in the poor responder group, MMP2 activity showed a reverse distribution. Likewise, significant differences were detected concerning the activity of TIMPs resulting in a negative correlation of TIMP1 activity with MMP2 activity (p = 0.044) and negative correlations of TIMP2 and TIMP3 with MMP9 activity (p = 0.007 and p = 0.006).
CONCLUSION: In contrast to mRNA or protein levels MMP and TIMP activities showed significant differences between the analyzed good and poor responder groups. A shift from MMP9 to predominant MMP2 activity is associated with poor response to chemotherapy suggesting that the ratio of MMP2/MMP9 activity might be a valuable and easily accessible marker to predict the response to chemotherapy in osteosarcoma.

Petrović N
miR-21 Might be Involved in Breast Cancer Promotion and Invasion Rather than in Initial Events of Breast Cancer Development.
Mol Diagn Ther. 2016; 20(2):97-110 [PubMed] Related Publications
Breast cancer (BC) is a heterogeneous disease that develops into a large number of varied phenotypes. One of the features used in its classification and therapy selection is invasiveness. MicroRNA-21 (miR-21) is considered to be an important element of BC invasiveness, and miR-21 levels are frequently increased in different tumor types compared with normal tissue, including the breast. Experimental and literature research has highlighted that miR-21 was always significantly elevated in every study that included invasive breast carcinomas compared with healthy breast tissue. The main goal of this research was to specify the predominant role of miR-21 in the different phases of BC pathogenesis, i.e. whether it was involved in the early (initiation), later (promotion), or late (propagation, progression) phases. Our second goal was to explain the roles of miR-21 targets in BC by an in silico approach and literature review, and to associate the importance of miR-21 with particular phases of BC pathogenesis through the action of its target genes. Analysis has shown that changes in miR-21 levels might be important for the later and/or late phases of breast cancerogenesis rather than for the initial early phases. Targets of miR-21 (TIMP3, PDCD4, PTEN, TPM1 and RECK) are also primarily involved in BC promotion and progression, especially invasion, angiogenesis and metastasis. miR-21 expression levels could perhaps be used in conjunction with the standard diagnostic parameters as an indicator of BC presence, and to indicate a phenotype likely to show early invasion/metastasis detection and poor prognosis.

Chen D, Yan W, Liu Z, et al.
Downregulation of miR-221 enhances the sensitivity of human oral squamous cell carcinoma cells to Adriamycin through upregulation of TIMP3 expression.
Biomed Pharmacother. 2016; 77:72-8 [PubMed] Related Publications
Aberrantly expressed microRNAs (miRNAs) are involved in oral tumorigenesis since they can alter the expression of proteins involved in cancer progression. It remains unclear whether miRNA-221 influences the resistance of human oral squamous cell carcinoma cells to Adriamycin. We therefore investigated the role of miR-221 in the sensitivity of oral squamous cell carcinoma cells to chemotherapy. Tca8113 and UM2 cells were treated with different concentrations of Adriamycin. Quantitative real-time PCR (qRT-PCR) revealed miR-221 upregulation after Adriamycin treatment of Tca8113 and UM2 cells. By using miR-221 inhibitor mimics, we found that depleting cells of miR-221 increases the sensitivity of the cells to Adriamycin. The expression of tissue inhibitor of metalloproteinase-3 (TIMP3), a target of miR-221, was decreased in cells treated with Adriamycin. TIMP3 depletion reversed the effect of a miR-221 inhibitor mimics on cell survival rates and apoptosis. Together, these results reveal that silencing of miR-221 enhances the sensitivity of human oral squamous cell carcinoma cells to Adriamycin through upregulation of TIMP3 expression.

Han XG, Li Y, Mo HM, et al.
TIMP3 regulates osteosarcoma cell migration, invasion, and chemotherapeutic resistances.
Tumour Biol. 2016; 37(7):8857-67 [PubMed] Related Publications
Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs) to limit degradation of the extracellular matrix. Low levels of TIMP3 have been demonstrated in cancer tissues at advanced clinical stages, with positive distant metastasis and chemotherapeutic resistance. We examined the role of TIMP3 in osteosarcoma (OS) cell invasiveness and chemoresistance. TIMP3 was overexpressed or knocked down in the human OS cell lines Saos2 and MG63. Cell migration and invasion capacities were then evaluated using Transwell assays, and resistance to cisplatin was assessed by CCK-8 assay and flow cytometry. Real-time PCR and western blotting were used to investigate activation of signaling pathways downstream of TIMP3. Overexpression of TIMP3 inhibited the migration and invasion of Saos2 and MG63 cells, while knockdown of TIMP3 had the opposite effect. Cell survival after exposure to cisplatin was inhibited by TIMP3 overexpression in both Saos2 and MG63 cells. Consistently, downregulation of TIMP3 gene expression significantly decreased the sensitivity of OS cells to cisplatin treatment. MMP1, MMP2, Bcl-2, and Akt1 were all downregulated following TIMP3 overexpression, while Bax and cleaved caspase-3 were upregulated. TIMP3 knockdown had opposite effects on the regulation of these genes. Taken together, our findings suggest TIMP3 as a new target for inhibition of OS progression and chemotherapeutic resistance.

Das AM, Koljenović S, Oude Ophuis CM, et al.
Association of TIMP3 expression with vessel density, macrophage infiltration and prognosis in human malignant melanoma.
Eur J Cancer. 2016; 53:135-43 [PubMed] Related Publications
AIMS: Several anti-tumour properties have been ascribed to the tissue inhibitor of matrix metalloproteinases-3 (TIMP3) gene, including inhibition of neovascularisation in tumour xenografts. Reduced protein expression has been linked to promoter hypermethylation and allelic loss of heterozygosity in various human malignancies. In melanoma-positive lymph nodes from patients, we evaluated the association between TIMP3 expression, vessel density, macrophage infiltration and potential correlations with disease-free survival (DFS) and overall survival (OS).
PATIENTS AND METHODS: TIMP3 expression was analysed by immunohistochemistry (IHC) in melanoma lymph node biopsies of stage III melanoma patients (n = 43). Blood vessel density and macrophage infiltration were quantitatively assessed and correlation with TIMP3 expression was investigated. Methylation status of the gene promoter was determined using methylation-specific polymerase chain reaction (MSP). Protein expression and promoter methylation status were investigated for associations with DFS and OS.
RESULTS: Reduced expression of TIMP3, as determined by IHC, was observed in 74% of the cases (32 in 43). A significant inverse correlation was observed between TIMP3 expression and vessel density (p = 0.031). Correlation between TIMP3 expression and macrophage infiltration was not statistically significant (p = 0.369). MSP analysis revealed methylation of the gene promoter in 18% (7 in 38) of the analysed cases. No differences in OS and DFS were observed between cases with high and low TIMP3 expression. Gene promoter methylation was significantly associated with both poor 5-year DFS (p = 0.024) and OS (p = 0.034).
CONCLUSIONS: Our data indicate that TIMP3 is a dominant negative regulator of angiogenesis in cutaneous melanoma and gene silencing by promoter methylation is associated with poor outcome.

Arriga R, Caratelli S, Coppola A, et al.
Enhancement of anti-leukemia activity of NK cells in vitro and in vivo by inhibition of leukemia cell-induced NK cell damage.
Oncotarget. 2016; 7(2):2070-9 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) cells induce, in vitro, NK cell abnormalities (NKCAs) including apoptosis and activating receptor down-regulation. The potential negative impact of AML cells on the therapeutic efficacy of NK cell-based strategies prompted us to analyze the mechanisms underlying NKCAs and to develop approaches to protect NK cells from NKCAs. NKCA induction by the AML leukemia cells target a subpopulation of peripheral blood NK cells and is interleukin-2 independent but is abrogated by a long-term culture of NK (LTNK) cells at 37°C. LTNK cells displayed a significantly enhanced ability to damage AML cells in vitro and inhibited the subcutaneous growth of ML-2 cells grafted into CB17 SCID mice. Actinomycin D restored the susceptibility of LTNK cells to NKCAs while TAPI-0, a functional analog of the tissue inhibitor of metalloproteinase (TIMP) 3, inhibits ML-2 cell-induced NKCAs suggesting that the generation of NK cell resistance to NKCAs involves RNA transcription and metalloproteinase (MPP) inactivation. This conclusion is supported by the reduced susceptibility to AML cell-induced NKCAs of LTNK cells in which TIMP3 gene and protein are over-expressed. This information may contribute to the rational design of targeted strategies to enhance the efficacy of NK cell-based-immunotherapy of AML with haploidentical NK cells.

Su CW, Huang YW, Chen MK, et al.
Polymorphisms and Plasma Levels of Tissue Inhibitor of Metalloproteinase-3: Impact on Genetic Susceptibility and Clinical Outcome of Oral Cancer.
Medicine (Baltimore). 2015; 94(46):e2092 [PubMed] Free Access to Full Article Related Publications
Oral cancer, the fourth most common cancer among men in Taiwan, is associated with environmental carcinogens. Tissue inhibitor of metalloproteinase-3 (TIMP3), a member of the TIMP family, is the only protein that binds to the extracellular matrix for suppressing cancer cell growth, angiogenesis, migration, and invasion. The association of TIMP3 polymorphism with oral cancer susceptibility, however, has not yet been reported. In this study, 1947 participants-1200 healthy male controls and 747 male patients with oral cancer-were recruited. Allelic discrimination of TIMP3 -1296 T > C (rs9619311), TIMP3 C > T (rs9862), and TIMP3 C > T (rs11547635) polymorphisms were assessed through real-time polymerase chain reaction. The authors discovered that individuals carrying the polymorphic rs9862 allele are more susceptible to oral cancer [odds ratio (OR), 1.5; 95% confidence interval (CI), 1.2-1.9; adjusted OR (AOR), 1.6; 95% CI, 1.2-2.1] after adjustment for betel quid chewing, alcohol, and tobacco consumption. Among 601 betel quid chewers, the TIMP3 polymorphism rs9862 T/T carriers had a 32.2-fold (95% CI, 20.2-51.3) increased oral cancer risk compared with those carrying C/C and not chewing betel quid. In addition, the authors observed a significant association between rs9862 variants and large tumors (OR, 1.5; 95% CI, 1.0-2.3) development. Moreover, TIMP3 plasma levels significantly increased in oral cancer patients who have large tumor or carry T allele rs9862 polymorphism. In conclusion, these results suggest that gene-environment interactions between the TIMP3 rs9862 polymorphisms and betel quid may alter oral cancer susceptibility and tumor growth in Taiwanese men.

Thakur S, Nabbi A, Klimowicz A, Riabowol K
Stromal ING1 expression induces a secretory phenotype and correlates with breast cancer patient survival.
Mol Cancer. 2015; 14:164 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Previous studies have established that levels of the Inhibitor of Growth 1(ING1) tumor suppressor are reduced in a significant proportion of different cancer types. Here we analyzed levels of ING1 in breast cancer patients to determine its prognostic significance as a biomarker for breast cancer prognosis.
METHODS: We used automated quantitative analysis (AQUA) to determine the levels of ING1 in the tumor associated stromal cells of 462 breast cancer samples. To better understand how high ING1 levels affect nearby epithelium, we measured the levels of cytokines and secreted matrix metalloproteases (MMPs), using an ELISA based assay in mammary fibroblasts overexpressing ING1. These cells were also used in a 3-dimensional co-culture with MCF7 cells to determine the effect of released MMPs and other cytokines on growing colonies.
RESULTS: We find that high levels of ING1 in stroma are associated with tumor grade (p = 0.001) and size (p = 0.02), and inversely associated with patient survival (p = 0.0001) in luminal, but not in non-luminal cancers, suggesting that high stromal ING1 promotes cancer development. In this group of patients ING1 could also predict patient survival and act as a biomarker (HR = 2.125). While ING1 increased or decreased the expression of different cytokines, ING1 also increased the levels of MMP1, MMP3 and MMP10 by 5-8 fold, and concomitantly decreased levels of the tissue inhibitors of metalloproteases TIMP2, TIMP3 and TIMP4 by 1.5-3.3 fold, resulting in significant increases in MMP activity as determined by zymography. Co-culturing of MCF7 cells with stromal cells expressing ING1 in 3-dimensional organoid cultures suggested that MCF7 colonies were less well defined, suggesting that secreted MMPs might promote migration.
CONCLUSION: These data indicate that stromal ING1 expression can predict the survival of patients with luminal breast cancer. High levels of ING1 in stromal cells can promote the development of breast cancer through increased expression and release of MMPs and down regulation of TIMPs, which may be an underlying mechanism of reduced patient survival.

Zhang W, Peng F, Zhou T, et al.
Targeted delivery of chemically modified anti-miR-221 to hepatocellular carcinoma with negatively charged liposomes.
Int J Nanomedicine. 2015; 10:4825-36 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. Gene therapy was established as a new strategy for treating HCC. To explore the potential delivery system to support the gene therapy of HCC, negatively charged liposomal delivery system was used to deliver miR-221 antisense oligonucleotide (anti-miR-221) to the transferrin (Tf) receptor over expressed HepG2 cells. The liposome exhibited a mean particle size of 122.5 nm, zeta potential of -15.74 mV, anti-miR-221 encapsulation efficiency of 70%, and excellent colloidal stability at 4°C. Anti-miR-221-encapsulated Tf-targeted liposome demonstrated a 15-fold higher delivery efficiency compared to nontargeted liposome in HepG2 cells in vitro. Anti-miR-221 Tf-targeted liposome effectively delivered anti-miR-221 to HepG2 cells, upregulated miR-221 target genes PTEN, P27(kip1), and TIMP3, and exhibited greater silencing efficiency over nontargeted anti-miR-221 liposome. After intravenous injection into HepG2 tumor-bearing xenografted mice with Cy3-labeled anti-miR-221 Tf-targeted liposome, Cy3-anti-miR-221 was successfully delivered to the tumor site and increased the expressions of PTEN, P27(kip1), and TIMP3. Our results demonstrate that the Tf-targeted negatively charged liposome could be a potential therapeutic modality in the gene therapy of human HCC.

Wieczorek E, Jablonowski Z, Tomasik B, et al.
MMP, VEGF and TIMP as prognostic factors in recurring bladder cancer.
Clin Biochem. 2015; 48(18):1235-40 [PubMed] Related Publications
OBJECTIVES: To investigate the clinical correlates and prognostic utility of MMP, VEGF and TIMP genes expression in bladder cancer (BCa) recurrence.
METHODS: Expression of MMP1, MMP2, MMP9, VEGFA and TIMP1, TIMP3 was analyzed by qRT-PCR using SYBR Green in peripheral blood leukocytes (PBLs) of BCa patients at two time points (diagnosis (n=40), and first recurrence (n=40)) and an age-matched group of healthy controls (n=100). Plasma concentrations of MMP1 (pro- and active forms) were measured using ELISA in BCa patients.
RESULTS: The expression of MMP1 mRNA was significantly lower in BCa patients with first recurrence compared to control (p=0.019). Expression of other genes did not differ significantly between the groups. MMP9 gene expression was associated with differentiation grade (p=0.043), with the highest expression in poorly differentiated tumors (G3) and was higher in smokers than in non-smokers (p=0.039) in BCa patients at diagnosis. The results at two time points showed that MMP9 and VEGFA genes expression was increased in patients with moderately differentiated BCa (p=0.029), and advanced pathologic stage (p=0.048), respectively. Moreover, gene expression of TIMP1 was increased for G3 (p=0.043), and was decreased for early recurrence (p=0.003).
CONCLUSIONS: Our study suggests that the expression of MMP9 in PBLs of BCa patients at diagnosis is associated with the differentiation grade of the BCa, and smoking status. Genes expression of MMP9, VEGFA and TIMP1 in PBLs may play a pivotal role in regulation of progression of BCa. Additionally, TIMP1 gene expression may be important factor for early recurrence of BCa.

Melnik BC
MiR-21: an environmental driver of malignant melanoma?
J Transl Med. 2015; 13:202 [PubMed] Free Access to Full Article Related Publications
Since the mid-1950's, melanoma incidence has been rising steadily in industrialized Caucasian populations, thereby pointing to the pivotal involvement of environmental factors in melanomagenesis. Recent evidence underlines the crucial role of microRNA (miR) signaling in cancer initiation and progression. Increased miR-21 expression has been observed during the transition from a benign melanocytic lesion to malignant melanoma, exhibiting highest expression of miR-21. Notably, common BRAF and NRAS mutations in cutaneous melanoma are associated with increased miR-21 expression. MiR-21 is an oncomiR that affects critical target genes of malignant melanoma, resulting in sustained proliferation (PTEN, PI3K, Sprouty, PDCD4, FOXO1, TIPE2, p53, cyclin D1), evasion from apoptosis (FOXO1, FBXO11, APAF1, TIMP3, TIPE2), genetic instability (MSH2, FBXO11, hTERT), increased oxidative stress (FOXO1), angiogenesis (PTEN, HIF1α, TIMP3), invasion and metastasis (APAF1, PTEN, PDCD4, TIMP3). The purpose of this review is to provide translational evidence for major environmental and individual factors that increase the risk of melanoma, such as UV irradiation, chemical noxes, air pollution, smoking, chronic inflammation, Western nutrition, obesity, sedentary lifestyle and higher age, which are associated with increased miR-21 signaling. Exosomal miR-21 induced by extrinsic and intrinsic stimuli may be superimposed on mutation-induced miR-21 pathways of melanoma cells. Thus, oncogenic miR-21 signaling may be the converging point of intrinsic and extrinsic stimuli driving melanomagenesis. Future strategies of melanoma treatment and prevention should thus aim at reducing the burden of miR-21 signal transduction.

Garcia PL, Miller AL, Kreitzburg KM, et al.
The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models.
Oncogene. 2016; 35(7):833-45 [PubMed] Related Publications
The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.

Siegel EM, Riggs BM, Delmas AL, et al.
Quantitative DNA methylation analysis of candidate genes in cervical cancer.
PLoS One. 2015; 10(3):e0122495 [PubMed] Free Access to Full Article Related Publications
Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and 22 women with normal cytology specimens. Bisulfite-modified genomic DNA was amplified and quantitative pyrosequencing completed for 10 genes (APC, CCNA, CDH1, CDH13, WIF1, TIMP3, DAPK1, RARB, FHIT, and SLIT2). A Methylation Index was calculated as the mean percent methylation across all CpG sites analyzed per gene (~4-9 CpG site) per sequence. A binary cut-point was defined at >15% methylation. Sensitivity, specificity and area under ROC curve (AUC) of methylation in individual genes or a panel was examined. The median methylation index was significantly higher in cases compared to controls in 8 genes, whereas there was no difference in median methylation for 2 genes. Compared to HPV and age, the combination of DNA methylation level of DAPK1, SLIT2, WIF1 and RARB with HPV and age significantly improved the AUC from 0.79 to 0.99 (95% CI: 0.97-1.00, p-value = 0.003). Pyrosequencing analysis confirmed that several genes are common targets for aberrant methylation in cervical cancer and DNA methylation level of four genes appears to increase specificity to identify cancer compared to HPV detection alone. Alterations in DNA methylation of specific genes in cervical cancers, such as DAPK1, RARB, WIF1, and SLIT2, may also occur early in cervical carcinogenesis and should be evaluated.

Dong M, Yang P, Hua F
MiR-191 modulates malignant transformation of endometriosis through regulating TIMP3.
Med Sci Monit. 2015; 21:915-20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Although aberrant expression of several miRNAs was found during the pathological development of endometriosis to endometriosis-associated ovarian cancer (EAOC), their roles are not fully understood. miR-191 is a miRNA significantly upregulated in endometriosis and EAOC patients. However, its downstream network is still not clear. This study explored its role in malignant transformation of endometriosis to EAOC.
MATERIAL AND METHODS: Tissues from 12 healthy controls, 12 patients with endometriomas, and 12 patients with EAOC were used to verify miR-191 expression by using qRT-PCR. Endometriosis cell line CRL-7566 and ovarian endometrioid carcinoma cell line CRL-11731 were used to explore the downstream regulative function of miR-191.
RESULTS: By using tissue and serum samples from healthy, endometriosis, and EAOC participants, we confirmed that miR-191 expression was significantly higher in endometriosis and EAOC participants. Interestingly, we also observed that TIMP3 expression was negatively correlated with miR-191 expression. Overexpressing miR-191 in CRL-7566 significantly increased cell proliferation and invasion, while miR-191 knockdown in CRL-11731 cells significantly decreased cell proliferation and invasion. These modulating effects of miR-191 are achieved through its regulation of TIMP3.
CONCLUSIONS: miR-191 can directly regulate TIMP3 expression, thereby affecting cell proliferation rate and invasion ability. The miR-191-TIMP3 axis might be critical in the malignant transformation of endometriosis to EAOC.

Melaiu O, Melissari E, Mutti L, et al.
Expression status of candidate genes in mesothelioma tissues and cell lines.
Mutat Res. 2015; 771:6-12 [PubMed] Related Publications
In order to broaden knowledge on the pathogenesis of malignant pleural mesothelioma (MPM), we reviewed studies on the MPM-transcriptome and identified 119 deregulated genes. However, there was poor consistency among the studies. Thus, the expression of these genes was further investigated in the present work using reverse transcriptase-quantitative PCR (RT-qPCR) in 15 MPM and 20 non-MPM tissue samples. Fifty-nine genes showed a statistically significant deregulation and were further evaluated in two epithelioid MPM cell lines (compared to MET-5A, a non-MPM cell line). Nine genes (ACSL1, CCNO, CFB, PDGFRB, SULF1, TACC1, THBS2, TIMP3, XPOT) were deregulated with statistical significance in both cell lines, 12 (ASS1, CCNB1, CDH11, COL1A1, CXADR, EIF4G1, GALNT7, ITGA4, KRT5, PTGIS, RAN, SOD1) in at least one cell line, whereas 7 (DSP, HEG1, MCM4, MSLN, NME2, NMU, TNPO2) were close but did not reach the statistical significance in any of the cell line. Patients whose MPM tissues expressed elevated mRNA levels of BIRC5, DSP, NME2, and THBS2 showed a statistically significant shorter overall survival. Although MPM is a poorly studied cancer, some features are starting to emerge. Novel cancer genes are suggested here, in particular those involved in cell-cell and cell-matrix interactions.

Chen M, Liu Y, Varley P, et al.
High-Mobility Group Box 1 Promotes Hepatocellular Carcinoma Progression through miR-21-Mediated Matrix Metalloproteinase Activity.
Cancer Res. 2015; 75(8):1645-56 [PubMed] Free Access to Full Article Related Publications
Liver inflammation plays a critical role in hepatocellular carcinoma (HCC) etiology. Damage-associated molecular patterns (DAMP), such as high-mobility group box 1 (HMGB1), and dysregulated miRNAs involved in inflammatory disease states, such as miR-21, may participate in the link between inflammation and cancer. We sought to determine the role of HMGB1 signaling in HCC tumor progression. We first document the concordant expression increase of HMGB1 and miR-21 in HCC cell lines and primary HCC tumor samples and subsequently show that HMGB1 stimulation results in overexpression of miR-21. These changes were found to be dependent on the IL6/STAT3 signaling axis. Invasion and migration of HCC cells in vitro were inhibited by both STAT3 and miR-21 antagonists, suggesting a role for this pathway in HCC tumor progression. We verified that HMGB1-induced expression of miR-21 in HCC provides a posttranscriptional repression of the matrix metalloproteinase (MMP) inhibitors RECK and TIMP3, which are known to impact HCC progression and metastases. Finally, we found that inhibition of miR-21 in murine HMGB1-overexpressing HCC xenografts led to reduced tumor MMP activity through released repression of the miR-21 targets RECK and TIMP3, which ultimately impeded tumor progression. The prototypical DAMP, HMGB1, is released during liver inflammation and provides a favorable environment for HCC growth. HMGB1 signaling increases miR-21 expression to mediate the enhanced activity of MMPs through RECK and TIMP3. These findings provide a novel mechanism for HMGB1-mediated HCC progression through the IL6/Stat3-miR-21 axis.

Arantes LM, de Carvalho AC, Melendez ME, et al.
Validation of methylation markers for diagnosis of oral cavity cancer.
Eur J Cancer. 2015; 51(5):632-41 [PubMed] Related Publications
PURPOSE: Activation of proto-oncogenes and inactivation of tumour suppressor genes are the major genetic alterations involved in carcinogenesis. The increase in methylation at the promoter region of a tumour suppressor gene can lead to gene inactivation, selecting cells with proliferative advantage. Thus, promoter hypermethylation is considered a marker in a variety of malignant tumours, including oral cavity.
EXPERIMENTAL DESIGN: The methylation pattern of eight genes was evaluated in 40 oral cavity squamous cell carcinomas (OSCCs) and 40 saliva samples from healthy individuals by Q-MSP. Different combinations of genes were also assessed in order to identify gene panels that could better distinguish between OSCC and saliva samples.
RESULTS: CCNA1, DAPK, DCC and TIMP3 methylation were highly specific for being found in the OSCC samples. Moreover, the combination of these genes improved detection when compared with single markers, reaching values of 92.5% for sensitivity and specificity (when using the panel CCNA1, DCC, TIMP3). Moreover, DAPK, DCC and TIMP3 were hypermethylated in nearly 90% of clinically T1 and T2 cases.
CONCLUSION: The pursuing of this panel of hypermethylated genes is an important tool for the detection of individuals with OSCC. Moreover, the identification of these markers in early stages of OSCC shows the feasibility of using the panel on saliva as possible biomarkers for early diagnosis. The lack of association between the methylation status of these genes and clinical characteristics shows that they are able to distinguish OSCC cases irrespective of social and clinical factors (gender, age, human papillomavirus (HPV) status, clinical stage, vascular embolisation and perineural invasion).

Martin del Campo SE, Latchana N, Levine KM, et al.
MiR-21 enhances melanoma invasiveness via inhibition of tissue inhibitor of metalloproteinases 3 expression: in vivo effects of MiR-21 inhibitor.
PLoS One. 2015; 10(1):e0115919 [PubMed] Free Access to Full Article Related Publications
Metastatic melanoma is the most aggressive form of this cancer. It is important to understand factors that increase or decrease metastatic activity in order to more effectively research and implement treatments for melanoma. Increased cell invasion through the extracellular matrix is required for metastasis and is enhanced by matrix metalloproteinases (MMPs). Tissue inhibitor of metalloproteinases 3 (TIMP3) inhibits MMP activity. It was previously shown by our group that miR-21, a potential regulator of TIMP3, is over-expressed in cutaneous melanoma. It was therefore hypothesized that increased levels of miR-21 expression would lead to decreased expression of TIMP3 and thereby enhance the invasiveness of melanoma cells. miR-21 over-expression in the melanoma cell lines WM1552c, WM793b, A375 and MEL 39 was accomplished via transfection with pre-miR-21. Immunoblot analysis of miR-21-overexpressing cell lines revealed reduced expression of TIMP3 as compared to controls. This in turn led to a significant increase in the invasiveness of the radial growth phase cell line WM1552c and the vertical growth phase cell line WM793b (p < 0.05), but not in the metastatic cell lines A375 or MEL 39. The proliferation and migration of miR-21 over-expressing cell lines was not affected. Reduced expression of TIMP3 was achieved by siRNA knockdown and significantly enhanced invasion of melanoma cell lines, mimicking the effects of miR-21 over-expression. Treatment of tumor cells with a linked nucleic acid antagomir to miR-21 inhibited tumor growth and increased tumor expression of TIMP3 in vivo in 01B74 Athymic NCr-nu/nu mice. Intra-tumoral injections of anti-miR-21 produced similar effects. This data shows that increased expression of miR-21 enhanced the invasive potential of melanoma cell lines through TIMP3 inhibition. Therefore, inhibition of miR-21 in melanoma may reduce melanoma invasiveness.

Paul-Samojedny M, Pudełko A, Suchanek-Raif R, et al.
Knockdown of the AKT3 (PKBγ), PI3KCA, and VEGFR2 genes by RNA interference suppresses glioblastoma multiforme T98G cells invasiveness in vitro.
Tumour Biol. 2015; 36(5):3263-77 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is the most common primary brain malignancy, having a very poor prognosis and is characterized by extensive brain invasion as well as resistance to the therapy. The phosphoinositide 3-kinase (PI3K)/Akt/PTEN signaling pathway is deregulated in GBM. Besides, florid vascularization and aberrantly elevated vascular endothelial growth factor (VEGF) occur very often. The present study was designed to examine the inhibitory effect of AKT3, PI3KCA, and VEGFR2 small interfering RNAs (siRNAs) on GBM cell invasiveness. T98G cells were transfected with AKT3, PI3KCA, and/or VEGFR2 siRNAs. VEGFR2 protein-positive cells were identified by flow cytometry using specific monoclonal anti-VEGFR2 antibodies. Alterations in messenger RNA (mRNA) expression of VEGF, VEGFR2, matrix metalloproteinases (MMPs) (MMP-2, MMP-9, MMP-13, MMP-14), tissue inhibitors of metalloproteinases (TIMPs) (TIMP-1, TIMP-3), c-Fos, c-Jun, hypoxia-inducible factor-1α (HIF-1α), ObRa, and cathepsin D genes were analyzed by qRT-PCR. Cells treated with specific siRNA were also analyzed for invasion using the Matrigel invasion assay. We have found significantly lower mRNA levels of MMPs, cathepsin D, VEGF, VEGFR2, HIF-1α, and c-Fos/c-Jun ratio, as well as significantly higher mRNA level of TIMPs in AKT3 and PI3KCA siRNA transfected cells compared to untransfected cells, while significantly lower mRNA levels of MMPs (MMP-2, MMP-9, MMP-14) and TIMP-1, as well as significantly higher mRNA level of TIMP-3, were shown only in cells transfected with VEGFR2 siRNA. The positive correlation between MMP-13 and ObRa mRNA copy number has been found. Summarizing, transfection of T98G cells with AKT3, PI3KCA, or VEGFR2 siRNAs leads to a significant reduction in cell invasiveness. The siRNA-induced AKT3, PI3KCA, and VEGFR2 mRNA knockdown may offer a novel therapeutic strategy to reduce the invasiveness of GBM cells.

Saraiva-Esperón U, Ruibal A, Herranz M
The contrasting epigenetic role of RUNX3 when compared with that of MGMT and TIMP3 in glioblastoma multiforme clinical outcomes.
J Neurol Sci. 2014; 347(1-2):325-31 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is the most frequent and malignant astrocytic glioma in the adult, with a survival rate at 5 years less than 5%. In the GBM pathogenesis, the importance of genes methylation involved in cell cycle, tumor suppression, DNA repair and genome integrity, as well as tumor invasion and apoptosis has been described. We analyzed epigenetic regulation involvement of two genes related with apoptosis: TIMP3 and RUNX3 in order to define a clinical profile and compare with the most studied gene in GBM: MGMT. Eighty samples from GBM patients were evaluated by methylation specific PCR (MSP). Data from each patient were collected from medical histories to relate survival rates with gene methylation patterns. Methylation percentages obtained were: MGMT 45%, RUNX3 30% and TIMP3 28%. The study of MGMT methylation had prognostic value in patients with glioblastoma multiforme because at 8 months, 28% of patients survived with the gene methylated, while none of them lived with the gene unmethylated (P=0.016). RUNX3 behavior was opposite to TIMP3 and MGMT. TIMP3action, in terms of patient's survival, was similar to that observed with MGMT, percentage of patients surviving at 8 months with the gene methylated was 27%, compared with 7% of those with the unmethylated gene; there being a tendency to statistical significance (p=0.09).

Wu H, Wang W, Xu H
Depletion of C3orf1/TIMMDC1 inhibits migration and proliferation in 95D lung carcinoma cells.
Int J Mol Sci. 2014; 15(11):20555-71 [PubMed] Free Access to Full Article Related Publications
In our previous study, we identified an association of high expression of c3orf1, also known as TIMMDC1 (translocase of inner mitochondrial membrane domain-containing protein 1), with metastatic characteristics in lung carcinoma cells. To investigate the preliminary function and mechanism of this mitochondrial protein, we depleted C3orf1 expression by introducing siRNA into 95D lung carcinoma cells. We demonstrated that C3orf1 depletion significantly suppressed 95D cell growth and migration. We confirmed C3orf1 localization in the inner mitochondrial membrane and showed that mitochondrial viability, membrane potential, and ATPase activity were remarkably reduced upon depletion of C3orf1. Microarray data indicated that genes involved in regulation of cell death, migration, and cell-cycle arrest were significantly altered after C3orf1 depletion for 48 h. The expression of genes involved in focal adhesion, ECM-receptor interaction, and p53-signaling pathways were notably altered. Furthermore, cell-cycle arrest genes such as CCNG2 and PTEN as well as genes involved in cell migration inhibition, such as TIMP3 and COL3A1, were upregulated after C3orf1 depletion in 95D cells. Concurrently, expression of the migration-promoting gene NUPR1 was markedly reduced, as confirmed by real-time PCR. We conclude that C3orf1 is critical for mitochondrial function, migration, and proliferation in 95D lung carcinoma cells. Depletion of C3orf1 inhibited cell migration and cell proliferation in association with upregulation of genes involved in cell-cycle arrest and cell migration inhibition. These results suggest that C3orf1 (TIMMDC1) may be a viable treatment target for lung carcinoma, and that further study of the role of this protein in lung carcinoma pathogenesis is justified.

Yu JL, Lv P, Han J, et al.
Methylated TIMP-3 DNA in body fluids is an independent prognostic factor for gastric cancer.
Arch Pathol Lab Med. 2014; 138(11):1466-73 [PubMed] Related Publications
CONTEXT: Fluid methylated DNA may be a suitable biomarker for cancer patients.
OBJECTIVE: To investigate whether circulating methylated tissue inhibitor of metalloproteinase 3 (TIMP-3) DNA in body fluids is a useful prognostic biomarker in gastric cancer (GC).
DESIGN: TIMP-3 methylation was detected by real-time methylation-specific polymerase chain reaction in tumor tissues, paired preoperative peritoneal washes (PPWs), and paired serum samples from 92 GC patients.
RESULTS: The frequency of TIMP-3 methylation was significantly elevated in GC tissues (63.04%; 58 of 92) compared with that in paired adjacent normal tissue (4.3%; 4 of 92) (P < .001). TIMP-3 methylation correlated closely with peritoneal metastasis and TNM stage (all P < .001). The frequency of TIMP-3 methylation in preoperative peritoneal washes and serum samples was 53.3% (49 of 92) and 58.7% (54 of 92), respectively. The Aζ values of the receiver operator characteristic curve for methylated TIMP-3 were 0.966 and 0.922 for serum and preoperative peritoneal washes, respectively, compared with those in GC tissues. The patients with elevated methylated TIMP-3 levels in body fluids had poorer disease-free survival rates than those without (all P < .001). Cox regression analysis showed that detection of methylated TIMP-3 DNA in body fluids was an independent risk factor for GC patients, with a remarkable decrease in disease-free survival 30 months after surgical resection of the gastric tumor.
CONCLUSION: Presence of methylated TIMP-3 DNA in body fluids is a useful biomarker for predicting the progression and prognosis of GC patients.

Mathsyaraja H, Thies K, Taffany DA, et al.
CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth.
Oncogene. 2015; 34(28):3651-61 [PubMed] Free Access to Full Article Related Publications
Metastasis of solid tumors is associated with poor prognosis and bleak survival rates. Tumor-infiltrating myeloid cells (TIMs) are known to promote metastasis, but the mechanisms underlying their collaboration with tumor cells remain unknown. Here, we report an oncogenic role for microRNA (miR) in driving M2 reprogramming in TIMs, characterized by the acquisition of pro-tumor and pro-angiogenic properties. The expression of miR-21, miR-29a, miR-142-3p and miR-223 increased in myeloid cells during tumor progression in mouse models of breast cancer and melanoma metastasis. Further, we show that these miRs are regulated by the CSF1-ETS2 pathway in macrophages. A loss-of-function approach utilizing selective depletion of the miR-processing enzyme Dicer in mature myeloid cells blocks angiogenesis and metastatic tumor growth. Ectopic expression of miR-21 and miR-29a promotes angiogenesis and tumor cell proliferation through the downregulation of anti-angiogenic genes such as Col4a2, Spry1 and Timp3, whereas knockdown of the miRs impedes these processes. miR-21 and miR-29a are expressed in Csf1r+ myeloid cells associated with human metastatic breast cancer, and levels of these miRs in CD115+ non-classical monocytes correlates with metastatic tumor burden in patients. Taken together, our results suggest that miR-21 and miR-29a are essential for the pro-tumor functions of myeloid cells and the CSF1-ETS2 pathway upstream of the miRs serves as an attractive therapeutic target for the inhibition of M2 remodeling of macrophages during malignancy. In addition, miR-21 and miR-29a in circulating myeloid cells may potentially serve as biomarkers to measure therapeutic efficacy of targeted therapies for CSF1 signaling.

Wang CY, Liou JP, Tsai AC, et al.
A novel action mechanism for MPT0G013, a derivative of arylsulfonamide, inhibits tumor angiogenesis through up-regulation of TIMP3 expression.
Oncotarget. 2014; 5(20):9838-50 [PubMed] Free Access to Full Article Related Publications
Tissue inhibitors of metalloproteinases 3 (TIMP3) were originally characterized as inhibitors of matrix metalloproteinases (MMPs), acting as potent antiangiogenic proteins. In this study, we demonstrated that the arylsulfonamide derivative MPT0G013 has potent antiangiogenic activities in vitro and in vivo viainducing TIMP3 expression. Treatments with MPT0G013 significantly inhibited endothelial cell functions, such as cell proliferation, migration, and tube formation, as well as induced p21 and cell cycle arrest at the G0/G1 phase. Subsequent microarray analysis showed significant induction of TIMP3 gene expression by MPT0G013, and siRNA-mediated blockage of TIMP3 up-regulation abrogated the antiangiogenic activities of MPT0G013 and prevented inhibition of p-AKT and p-ERK proteins. Importantly, MPT0G013 exhibited antiangiogenic activities in in vivo Matrigel plug assays, inhibited tumor growth and up-regulated TIMP3 and p21 proteins in HCT116 mouse xenograft models. These data suggest potential therapeutic application of MPT0G013 for angiogenesis-related diseases such as cancer.

Lu HG, Zhan W, Yan L, et al.
TET1 partially mediates HDAC inhibitor-induced suppression of breast cancer invasion.
Mol Med Rep. 2014; 10(5):2595-600 [PubMed] Related Publications
Histone deacetylases (HDACs) are important in chromatin remodeling and epigenetic regulation of gene expression. Histone deacetylase inhibitors (HDACi) have highly effective anti-metastatic and anti-angiogenic activity in various types of cancer, while the molecular mechanisms involved in this process are not fully understood. In the present study, trichostatin A (TSA), a HDACi, was found to suppress MCF-7 breast carcinoma cell invasion and upregulate TET1 expression in a dose-dependent manner. TET1, a dioxygenase involved in cytosine demethylation, is downregulated during breast cancer progression. TET1 knockdown in MCF-7 cells facilitates cell invasion, inhibits the expression of tissue inhibitors of metalloproteinase 2/3 (TIMP2/3) and promotes matrix metalloproteinases (MMP) 2/9 transcriptional activity. Importantly, TET1 depletion impaired the inhibitory effect of TSA on breast cancer cell invasion. Together, these results illustrated a mechanism by which TET1 partially mediates HDACi elicited suppression of breast cancer invasion.

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