Gene Summary

Gene:TIMP2; TIMP metallopeptidase inhibitor 2
Aliases: DDC8, CSC-21K
Summary:This gene is a member of the TIMP gene family. The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix. In addition to an inhibitory role against metalloproteinases, the encoded protein has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. As a result, the encoded protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodelling of the extracellular matrix. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:metalloproteinase inhibitor 2
Source:NCBIAccessed: 30 August, 2019


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 (1994-2019)
Graph generated 30 August 2019 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.

Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

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: TIMP2 (cancer-related)

Zhang Y, Zhao Z, Li S, et al.
Inhibition of miR‑214 attenuates the migration and invasion of triple‑negative breast cancer cells.
Mol Med Rep. 2019; 19(5):4035-4042 [PubMed] Free Access to Full Article Related Publications
Triple‑negative breast cancer (TNBC) is a subtype of breast cancer. MicroRNA (miR)‑214 is closely associated with controlling the development of tumor cells; therefore, in the present study, the target gene and effects of miR‑214 on TNBC cells were explored. Luciferase activity was examined by luciferase reporter assay. The viability, invasion and migration of MDA‑MB‑231 TNBC cells were measured using Cell Counting kit‑8, Transwell and wound‑healing assays, respectively. The expression levels of various factors were determined using reverse transcription‑quantitative polymerase chain reaction and western blotting. The results demonstrated that the expression levels of miR‑214 were higher and the levels of α1‑antitrypsin (α1‑AT) were lower in TNBC tissues compared with in normal tissues. Subsequently, α1‑AT was revealed to be a target of miR‑214. Furthermore, inhibition of miR‑214 decreased cell viability, invasion and migration, enhanced the expression of E‑cadherin and tissue inhibitor of metalloproteinases‑2, and reduced the expression of metastatic tumour antigen 1 and matrix metalloproteinase‑2. Inhibition of miR‑214 also significantly downregulated the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR), and markedly downregulated that of phosphoinositide 3‑kinase (PI3K); however, the expression levels of total PI3K, Akt and mTOR remained stable in all groups. Taken together, these findings indicated that α1‑AT may be a target of miR‑214. Downregulation of miR‑214 markedly suppressed the viability, migration and invasion of MDA‑MB‑231 cells, and inhibited the PI3K/Akt/mTOR pathway. These findings suggested that miR‑214 targeting α1‑AT may be a potential mechanism underlying TNBC development.

Chen C, Shan H
Keratin 6A gene silencing suppresses cell invasion and metastasis of nasopharyngeal carcinoma via the β‑catenin cascade.
Mol Med Rep. 2019; 19(5):3477-3484 [PubMed] Free Access to Full Article Related Publications
Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer. This study aimed to study the mechanisms of ectopic keratin 6A (KRT6A) in NPC. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting were performed to detect KRT6A levels in NPC cell lines (C666‑1, 5‑8F and SUNE‑1) and a nasopharyngeal epithelial cell line (NP69, as a control). After SUNE‑1 NPC cells had been silenced by KRT6A, cell viability, metastasis and invasion were determined using Cell Counting Kit‑8, wound healing and Transwell assays, respectively. KRT6A levels, metastasis‑associated factors and the Wnt/β‑catenin pathway were measured using RT‑qPCR and western blotting. It was demonstrated that KRT6A was upregulated in all detected NPC cells, among which KRT6A was the highest in SUNE‑1 cells. In SUNE‑1 cells, cell viability was inhibited at 24 and 48 h, and that cell metastasis and invasion were demonstrated to be suppressed by KRT6A silencing. Both the mRNA and protein levels of KRT6A, matrix metalloproteinase (MMP)‑2, MMP‑9, β‑catenin, lymphoid enhancer binding factor 1 and T‑cell specific factor 4 were reduced in the small interfering (si)KRT6A group. However, the results demonstrated that the levels of epithelial‑cadherin and tissue inhibitor of metalloproteinase‑2 (TIMP‑2) were promoted in the siKRT6A group. The activation of the Wnt/β‑catenin pathway by lithium chloride reversed the effect of si‑KRT6A by modulating the expression of MMP‑2/9 and TIMP2. It was observed that KRT6A silencing suppressed cell invasion and metastasis of NPC via the β‑catenin cascade. Together these results provide important insights into a novel approach for the diagnosis and treatment of NPC.

Kushlinskii NE, Gershtein ES, Ivannikov AA, et al.
Clinical Significance of Matrix Metalloproteinases in Blood Plasma of Patients with Gastric Cancer.
Bull Exp Biol Med. 2019; 166(3):373-376 [PubMed] Related Publications
Plasma levels of MMP-2, MMP-7, and MMP-9 and their tissue inhibitor TIMP-2 were measured in 89 patients with gastric cancer and the relationship between these parameters and the main clinical morphological characteristics of the disease was analyzed. Plasma levels of the proteins were measured using standard direct ELISA kits. The level of MMP-7 in patients with gastric cancer was significantly higher than in the control group (medians 2.7 and 1.2 ng/ml, respectively; p<0.01), but only in 51% patients this parameter surpassed the upper threshold normal value (2.35 ng/ml; 95% percentile of control). The level of MMP-9 in gastric cancer patients was lower than in control group by 1.6 times (medians 167 and 267 ng/ml, respectively; p<0.01). Plasma levels of MMP-2 and TIMP-2 in patients with gastric cancer and healthy subjects were similar. No appreciable associations of plasma matrixins and TIMP-2 with the main clinical morphological characteristics of the disease were detected. The patients were followed up for 8 to 85 months (median 70.8 months). Low level of MMP-2 and high level of MMP-7 in the plasma proved to be unfavorable prognostic factors for overall survival. At MMP-2<268 ng/ml, the 5-year overall survival was 32% vs. 60% for patients with the marker level higher than this threshold value (p=0.016). The differences in overall survival in relation to their MMP-7 levels for 5-year observation did not surpass 16% (39% at marker level >2.7 ng/ml and 55% at lower level; p=0.048). Plasma levels of MMP-2 and TIMP-2 were not significantly associated with overall survival. Multivariate analysis showed that only T index (p=0.034) and plasma MMP-7 level (p=0.007) were essential for overall survival. The increase in plasma or serum MMP-7 levels is a universal phenomenon in tumors of different histogenesis, which precluded the use of this parameter as a specific diagnostic marker of gastric cancer. At the same time, it could be useful for monitoring the treatment efficiency and detection of relapses. In addition, high plasma level of MMP-7 remained an independent factor of unfavorable prognosis for overall survival of patients with gastric cancer.

Kochurova EV
Comparative Role of Matrixins in Diagnostics of Parotid Gland Tumors.
Bull Exp Biol Med. 2019; 166(3):383-385 [PubMed] Related Publications
The benign and malignant neoplasms in parotid gland have similar clinical presentations despite different tumor growth rates. The study compared the clinical and morphological data as well as the results of ELISA for MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 in salivary fluid yielded during primary examination of the patients with pleomorphic adenoma and adenocarcinoma of parotid gland. The examined biomarkers detected in salivary fluid in patients with various cancer types differed significantly (p≤0.05). The correlations between clinical identification of adenoma or adenocarcinoma, on the one hand, and the levels of MMP-8, TIMP-1, and TIMP-2, on the other hand, makes it possible to use the latter as biomarkers for early detection and comprehensive noninvasive differential diagnostics of these neoplasms.

Wang Y, Yang Q, Cheng Y, et al.
Myosin Heavy Chain 10 (MYH10) Gene Silencing Reduces Cell Migration and Invasion in the Glioma Cell Lines U251, T98G, and SHG44 by Inhibiting the Wnt/β-Catenin Pathway.
Med Sci Monit. 2018; 24:9110-9119 [PubMed] Free Access to Full Article Related Publications
BACKGROUND The myosin heavy chain 10 or MYH10 gene encodes non-muscle myosin II B (NM IIB), and is involved in tumor cell migration, invasion, extracellular matrix (ECM) production, and epithelial-mesenchymal transition (EMT). This study aimed to investigate the effects of the MYH10 gene on normal human glial cells and glioma cell lines in vitro, by gene silencing, and to determine the signaling pathways involved. MATERIAL AND METHODS The normal human glial cell line HEB, and the glioma cell lines, U251, T98G, and SHG44 were studied. Plasmid transfection silenced the MYH10 gene. The cell counting kit-8 (CCK-8) assay evaluated cell viability. Cell migration and invasion were evaluated using scratch and transwell assays. Western blot measured the protein expression levels, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels, for MYH10, metastasis-associated protein 1 (MTA-1), matrix metalloproteinase (MMP)-1, MMP-9, tissue inhibitor of metalloproteinases 2 (TIMP2), collagen 1, E-cadherin, vimentin, Wnt3a, β-catenin, and cyclin D1. RESULTS The MYH10 gene was overexpressed in U251, T98G, and SHG44 cells. MYH10 expression was down-regulated following siMYH10 plasmid interference, which also inhibited glioma cell migration and invasion. MYH10 gene silencing resulted in reduced expression of MTA-1, MPP-2, MMP-9 and vimentin, and increased expression of TIMP-2, E-cadherin and collagen 1 at the protein and mRNA level, and inhibited the Wnt/β-catenin pathway. CONCLUSIONS In human glioma cell lines, silencing the MYH10 gene reduced cell migration and invasion, by inhibiting the Wnt/β-catenin pathway, which may regulate the ECM and inhibit EMT in human glioma.

Fouad H, Salem H, Ellakwa DE, Abdel-Hamid M
MMP-2 and MMP-9 as prognostic markers for the early detection of urinary bladder cancer.
J Biochem Mol Toxicol. 2019; 33(4):e22275 [PubMed] Related Publications
The present study assessed protein and gene expression levels of tissue inhibitor of metalloproteinase-2 (TIMP-2), matrix metalloproteinase-2 (MMP-2), and MMP-9 in urine and blood samples of 50 patients with bladder carcinoma. The expression of TIMP-2, MMP-2, and MMP-9 levels with tumor stage and grade was also assessed. Results showed that the expression levels of MMP-2 and MMP-9 in both blood and urine were significantly elevated in group 1 when compared with groups 2 and 3 healthy subjects. The discriminatory ability in the diagnosis of bladder carcinoma of MMP-2 and MMP-9 expression was confirmed by receiver operating characteristic curve analysis that revealed a sensitivity and specificity of 100%. MMP-2 and MMP-9 levels were not correlated with grade or stage of the tumor. With respect to TIMP-2 blood and urine levels, results showed a significant decrease in gene expression levels in bladder carcinoma group, whereas, TIMP-2 protein showed a significant increase in bladder carcinoma.

Li Q, Xing W, Gong X, Wang Y
Long Non-Coding RNA Urothelial Carcinoma Associated 1 Promotes Proliferation, Migration and Invasion of Osteosarcoma Cells by Regulating microRNA-182.
Cell Physiol Biochem. 2018; 51(3):1149-1163 [PubMed] Related Publications
BACKGROUND/AIMS: Previous studies demonstrated the oncogenic roles of lncRNA UCA1 in osteosarcoma. This study aimed to explore the internal molecular mechanism of UCA1 on promoting osteosarcoma cell proliferation, migration and invasion.
METHODS: qRT-PCR was conducted to measure the expression levels of UCA1, miR-182 and TIMP2. Cell transfection was used to change the expression levels of UCA1, miR-182 and TIMP2. Cell viability, migration, invasion and apoptosis were measured using CCK-8 assay, two-chamber migration (invasion) assay and Guava Nexin assay, respectively. The associations between UCA1, miR-182 and iASPP were analyzed by dual luciferase activity assay. The protein expression levels of key factors involved in cell apoptosis, PI3K/AKT/GSK3β pathway and NF-κB pathway, as well as p53, Rb, RECQ family and iASPP were evaluated by western blotting.
RESULTS: UCA1 was highly expressed in osteosarcoma MG63 and OS-732 cells. Knockdown of UCA1 inhibited OS-732 cell viability, migration and invasion, but promoted cell apoptosis. miR-182 was up-regulated in OS-732 cells after UCA1 knockdown and participated in the effects of UCA1 on OS-732 cells. TIMP2 was downstream factor of miR-182 and involved in the regulatory roles of miR-182 on OS-732 cell viability, migration, invasion, apoptosis, as well as PI3K/AKT/GSK3β and NF-κB pathways. UCA1 knockdown up-regulated p53, Rb and RECQL5 levels in OS-732 cells, while down-regulated the expression of iASPP. TGF-β or TNF-α treatment could enhance the expression of UCA1 in OS-732 cells.
CONCLUSION: Our research verified that UCA1 exerted oncogenic roles in osteosarcoma cells by regulating miR-182 and TIMP2, as well as PI3K/AKT/GSK3β and NF-κB pathways.

Jiang L, Qian J, Yang Y, Fan Y
Knockdown of MON1B Exerts Anti-Tumor Effects in Colon Cancer In Vitro.
Med Sci Monit. 2018; 24:7710-7718 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Colon cancer is one of the most common cancers in the world. We performed the present study to determine the molecular mechanism of MON1B in colon cancer cells. MATERIAL AND METHODS Colon cancer tissues and adjacent normal tissues were collected from 34 colon cancer patients. MON1B-silenced LoVo colon cancer cells were constructed. RT-qPCR and Western blot analysis were used to detect mRNA and protein levels, respectively, of colon cancer tissues and cells. Cell counting kit-8 (CCK-8), wound healing, and Transwell assays were used to detect viability, migration, and invasion, respectively, of colon cancer cells. RESULTS The mRNA and protein levels of MON1B were higher in colon cancer tissues and human colon cancer cell lines (HT-29, SW480, COLO205, LoVo). Cell proliferation, migration, and invasion abilities were all inhibited when MON1B was silenced in LoVo colon cancer cells. Both the mRNA and protein levels of tissue inhibitor of metalloproteinase (TIMP)-2 and iκB were increased, while that of matrix metalloproteinases (MMP)-2, MMP-9, metastasis-associated genes (MTA)-1, nuclear factor-kappa B (NF-κB), and chemokine receptor type (CXCR)-4 was decreased when MON1B was silenced. CONCLUSIONS MON1B interference exerted anti-tumor effect in colon cancer in vitro.

Chen A, Liu S, Lu X, et al.
Inhibition of microRNA‑939 suppresses the development of human non‑small cell lung cancer via the upregulation of tissue inhibitor of metalloproteinases 2.
Mol Med Rep. 2018; 18(6):4831-4838 [PubMed] Free Access to Full Article Related Publications
Numerous microRNAs (miRNA/miRs) have been reported to be associated with the initiation and progression of non‑small cell lung cancer (NSCLC). The aim of the present study was to examine the expression and biological role of miR‑939 in human NSCLC, in vitro. Reverse transcription‑quantitative polymerase chain reaction analysis was used to evaluate the expression of miR‑939 in NSCLC tissues. Cell Counting Kit‑8, 5‑ethynyl‑29‑deoxyuridine and Transwell assays were also used to determine the effects of miR‑939 on tumor cell proliferation and invasion in two human NSCLC cell lines (H1299 and SPCA1). Furthermore, tissue inhibitor of metalloproteinases 2 (TIMP2) was confirmed to be a target of miR‑939 by luciferase reporter assay, western blotting and bioinformatics analysis. Following downregulation of miR‑939 expression, cell proliferative and invasive abilities were significantly suppressed. Collectively, these findings indicated that the knockdown of miR‑939 may inhibit cell proliferation and invasion by regulating the expression of TIMP2 in NSCLC cells. Thus, miR‑939 may be a potential target in the treatment of NSCLC, although this requires further investigation.

Bruno A, Bassani B, D'Urso DG, et al.
Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer.
FASEB J. 2018; 32(10):5365-5377 [PubMed] Related Publications
NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solid malignancies, NK cells have compromised functions. We have previously reported that lung tumor-associated NK cells (TANKs; peripheral blood) and tumor-infiltrating NK cells (TINKs) show proangiogenic, decidual NK-like (dNK) phenotype. In this study, we functionally and molecularly investigated TINKs and TANKs from blood and tissue samples of patients with colorectal cancer (CRC), a neoplasm in which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINKs/TANKs showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-like NK polarization toward the CD56

Wang F, Sun Y
Overexpression of Myosin Phosphatase Target Subunit 1 (MYPT1) Inhibits Tumor Progression and Metastasis of Gastric Cancer.
Med Sci Monit. 2018; 24:2508-2517 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Myosin phosphatase target subunit 1 (MYPT1) serves as a subgroup of myosin phosphatases, and is frequently low-expressed in human cancers. However, little is known about the effects of MYPT1 in gastric cancer (GC). MATERIAL AND METHODS In our study, MYPT1 expression was detected by quantitative real-time reverse transcription PCR (qRT-PCR) in GC tissues, different advanced pathological stages of GC tissues, and preoperative and postoperative patients. Kaplan-Meier analysis was used to measure the overall survival of GC patients. MYPT1 expression was analyzed by qRT-PCR and Western blot assays in GES-1 cells and GC cells. Cell proliferation, cycle, and migration and invasion abilities were detected by CCK-8, flow cytometry, and Transwell assays. E-cadherin, TIMP-2, MMP-2, MMP-9 RhoA, and p-RhoA expressions were assessed by qRT-PCR and Western blot assays in treated SNU-5 cells. RESULTS Our results indicated that MYPT1 was down-regulated in GC tissues and cells, and is related to clinical stages and overall survival of GC. Functional research demonstrated that overexpression of MYPT1 can inhibit cell proliferation, cell cycle progression, and migration and invasion of GC cells. Many studies on mechanisms reported that overexpression of MYPT1 dramatically improved the expression levels of cell cycle-related genes (Cyclin D1 and c-myc), significantly increased epithelial marker (E-cadherin) expression, and decreased invasion-associated genes (TIMP-2 and MMP-2) expressions in SNU-5 cells. In addition, we found that MYPT1 suppressed RhoA phosphorylation. CONCLUSIONS We verified that MYPT1 inhibits GC cell proliferation and metastasis by regulating RhoA phosphorylation.

Guo Y, Jiang Y, Sang M, Xu C
RETRACTED: Down-regulation of miR-373 increases the radiosensitivity of lung cancer cells by targeting TIMP2.
Int J Biochem Cell Biol. 2018; 99:203-210 [PubMed] Related Publications
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. The image analysis run on the Western blots in Figures 4 and 6 revealed that the images have been manipulated. Manipulating images in any part of a publication is ethically not acceptable.

Chen Z, Zhu J, Zhu Y, Wang J
MicroRNA-616 promotes the progression of ovarian cancer by targeting TIMP2.
Oncol Rep. 2018; 39(6):2960-2968 [PubMed] Related Publications
MicroRNAs (miRNAs), a group of short (~20 nt) non‑coding RNAs, play critical roles in the development and progression of ovarian cancer (OC). The role of miR‑616, a recently identified cancer-associated miRNA, has never been examined in OC before. The present study demonstrated that the level of miR‑616 was increased in OC tissues. A high miR‑616 level was associated with poor tumor differentiation and advanced tumor-node-metastasis (TNM) stage. Survival analysis revealed that an elevated level of miR‑616 was associated with poor prognosis of OC patients as demonstrated by decreased overall survival (OS) and disease‑free survival (DFS). Overexpression of miR‑616 promoted the migration, invasion as well as epithelial-mesenchymal transition (EMT) of A2780 cells. Knockdown of miR‑616 inhibited these biological functions. Immunohistochemical (IHC) staining revealed that OC tissues with high miR‑616 levels exhibited a significantly decreased level of E‑cadherin and an increased level of N‑cadherin. Furthermore, tissue inhibitor of metalloproteinases 2 (TIMP2) was confirmed to be a direct downstream target of miR‑616. Inhibition of TIMP2 expression was required for the promoting effects of miR‑616 on the metastasis and EMT of OC cells. Collectively, this study revealed that miR‑616 promoted the progression of OC by enhancing cell migration, invasion and EMT.

Yamada Y, Chowdhury A, Schneider JP, Stetler-Stevenson WG
Macromolecule-Network Electrostatics Controlling Delivery of the Biotherapeutic Cell Modulator TIMP-2.
Biomacromolecules. 2018; 19(4):1285-1293 [PubMed] Free Access to Full Article Related Publications
Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an endogenous 22 kDa proteinase inhibitor, demonstrating antitumorigenic, antimetastatic and antiangiogenic activities in vitro and in vivo. Recombinant TIMP-2 is currently undergoing preclinical testing in multiple, murine tumor models. Here we report the development of an inert, injectable peptide hydrogel matrix enabling encapsulation and sustained release of TIMP-2. We studied the TIMP-2 release profile from four β-hairpin peptide gels of varying net electrostatic charge. A negatively charged peptide gel (designated AcVES3) enabling encapsulation of 4 mg/mL of TIMP-2, without effects on rheological properties, facilitated the slow sustained release (0.9%/d) of TIMP-2 over 28 d. Released TIMP-2 is structurally intact and maintains the ability to inhibit MMP activity, as well as suppress lung cancer cell proliferation in vitro. These findings suggest that the AcVES3 hydrogel will be useful as an injectable vehicle for systemic delivery of TIMP-2 in vivo for ongoing preclinical development.

Nagai H, Hasegawa S, Uchida F, et al.
MicroRNA-205-5p suppresses the invasiveness of oral squamous cell carcinoma by inhibiting TIMP‑2 expression.
Int J Oncol. 2018; 52(3):841-850 [PubMed] Related Publications
MicroRNAs (miRNAs or miRs) play important roles in carcinogenesis. The miRNA, miR-205-5p, has been reported to suppress the growth of various types of tumor; however, its functional contribution to oral squamous cell carcinoma (OSCC) is not yet clear. Thus, this study was conducted to determine the miRNA expression signatures in OSCC and to investigate the functional role of miR‑205‑5p in OSCC cells. We measured miR‑205‑5p expression by RT-qPCR, and examined the function of miR‑205‑5p by transfecting a miR‑205‑5p mimic or inhibitor into OSCC cells and measuring cell proliferation, migration and invasiveness. Genes targeted by miR‑205‑5p were identified using the TargetScan database and verified by western blot analysis, luciferase reporter assay and ELISA. We found that miR‑205‑5p was significantly downregulated in OSCC cell lines and tissue specimens. Following transfection of miR‑205‑5p mimic or inhibitor into the cancer cell lines, miR‑205‑5p overexpression significantly suppressed cancer cell migration and invasion. We further demonstrated that miR‑205‑5p directly targeted and regulated the tissue inhibitor of metalloproteinases‑2 (TIMP‑2) gene. The silencing of TIMP‑2 suppressed cancer cell invasion and the activation of pro‑matrix metalloproteinase‑2 (pro‑MMP‑2). These results suggest that TIMP‑2 promotes tumor progression, and that miR‑205‑5p directly regulates TIMP‑2, thereby suppressing pro‑MMP‑2 activation and inhibiting OSCC cell invasiveness. Our data describing the pathways regulated by miR‑205‑5p provide new insight into the mechanisms responsible for OSCC development and metastasis.

Hasegawa T, Glavich GJ, Pahuski M, et al.
Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate.
Mol Cancer Res. 2018; 16(4):669-681 [PubMed] Free Access to Full Article Related Publications
Prostate cancer afflicts 1 in 7 men and is the second leading cause of male cancer-related deaths in the United States. MicroRNAs (miRNAs), an extensive class of approximately 22 nucleotide noncoding RNAs, are often aberrantly expressed in tissues and fluids from prostate cancer patients, but the mechanisms of how specific miRNAs regulate prostate tumorigenesis and metastasis are poorly understood. Here, miR-888 was identified as a novel prostate factor that promotes proliferation and migration. miR-888 resides within a genomic cluster of 7 miRNA genes (

Ou Y, Wu Q, Wu C, et al.
Migfilin promotes migration and invasion in glioma by driving EGFR and MMP-2 signalings: A positive feedback loop regulation.
J Genet Genomics. 2017; 44(12):557-565 [PubMed] Related Publications
Glioma is the most common type of primary brain tumors in the central nervous system (CNS). Migfilin occurs in human glioma and enhances cellular motility via the epidermal growth factor receptor (EGFR) pathway. However, the underlying molecular mechanism is not fully understood. In this study, we found that Migfilin promoted matrix metalloproteinase-2 (MMP-2) activity, and restrained the expression of tissue inhibitor of metalloproteinase 2 (TIMP2), which is an MMP-2 inhibitor. Functional and structural studies showed that the LIM1 domain of Migfilin was required for Migfilin-mediated TIMP2 expression inhibition and MMP-2 activity, and was also necessary in promoting cell motility. Furthermore, Migfilin-induced EGFR phosphorylation was greatly reduced by MMP-2 inhibitor (GM6001) or siRNA, while Migfilin-induced MMP-2 activation was also blocked by the EGFR inhibitor (AG1478) or siRNA. MMP-2 and EGFR inhibitors and their siRNAs can block Migfilin-induced migration and invasion, respectively. These results demonstrated that EGFR and MMP-2 signalings may form a positive feedback loop to enhance Migfilin-induced migration and invasion. Finally, we detected that the expression of Migfilin, EGFR phosphorylation (Tyr1173) and MMP-2 activity had a positive correlation in the clinical glioma sample. Taken together, these results suggest that Migfilin is a critical regulator in cellular motility by driving the EGFR-MMP-2 feedback loop, and may be considered as a potential therapeutic target in glioma.

Sandoval-Bórquez A, Polakovicova I, Carrasco-Véliz N, et al.
MicroRNA-335-5p is a potential suppressor of metastasis and invasion in gastric cancer.
Clin Epigenetics. 2017; 9:114 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiple aberrant microRNA expression has been reported in gastric cancer. Among them, microRNA-335-5p (miR-335), a microRNA regulated by DNA methylation, has been reported to possess both tumor suppressor and tumor promoter activities.
RESULTS: Herein, we show that miR-335 levels are reduced in gastric cancer and significantly associate with lymph node metastasis, depth of tumor invasion, and ultimately poor patient survival in a cohort of Amerindian/Hispanic patients. In two gastric cancer cell lines AGS and, Hs 746T the exogenous miR-335 decreases migration, invasion, viability, and anchorage-independent cell growth capacities. Performing a PCR array on cells transfected with miR-335, 19 (30.6%) out of 62 genes involved in metastasis and tumor invasion showed decreased transcription levels. Network enrichment analysis narrowed these genes to nine (PLAUR, CDH11, COL4A2, CTGF, CTSK, MMP7, PDGFA, TIMP1, and TIMP2). Elevated levels of PLAUR, a validated target gene, and CDH11 were confirmed in tumors with low expression of miR-335. The 3'UTR of CDH11 was identified to be directly targeted by miR-335. Downregulation of miR-335 was also demonstrated in plasma samples from gastric cancer patients and inversely correlated with DNA methylation of promoter region (Z = 1.96,
CONCLUSIONS: Comprehensive evaluation of metastasis and invasion pathway identified a subset of associated genes and confirmed PLAUR and CDH11, both targets of miR-335, to be overexpressed in gastric cancer tissues. DNA methylation of miR-335 may be a promissory strategy for non-invasive approach to gastric cancer.

Liu Y, Nan F, Lu K, et al.
Identification of key genes in endometrioid endometrial adenocarcinoma via TCGA database.
Cancer Biomark. 2017; 21(1):11-21 [PubMed] Related Publications
BACKGROUND: Understanding the molecular mechanisms is important in development and therapy of endometrioid endometrial adenocarcinoma.
OBJECTIVE: To identify key genes in endometrioid endometrial adenocarcinoma.
METHODS: The data of mRNA, miRNA and DNA methylation were downloaded from The Cancer Genome Atlas (TCGA) database and differential analysis was performed. Then, bioinformatic analysis was used to explore the regulatory mechanisms of miRNA and DNA methylation on gene expression. The regulatory network between differentially expressed miRNAs and target genes was established. Finally, the quantitative RT-PCR was applied to validate the bioinformatics results.
RESULTS: We obtained biological omics data of 381 patients with endometrioid endometrial adenocarcinoma from TCGA data portal. After data processing, up to 2068 DEGs and 69 differentially expressed miRNAs were identified. Prediction and correlation analysis revealed that 175 DEGs that were not only the target genes but also negatively correlated with the screened differentially expressed miRNAs. After the integrated analysis of differentially methylated CpG islands and DEGs, 16 related genes were obtained. The quantitative RT-PCR results were roughly consistent with the bioinformatics analysis.
CONCLUSIONS: The altered DEGs (ZEB1, ZEB2, TIMP2, TCF4, CYP1B1, PITX1, PITX2, ZNF154 and TSPYL5) may be involved in tumor differentiation of endometrioid endometrial adenocarcinoma and could be used as potential therapeutic targets for the disease.

Pençe S, Özbek E, Ozan Tiryakioğlu N, et al.
rs3918242 variant genotype frequency and increased TIMP-2 and MMP-9 expression are positively correlated with cancer invasion in urinary bladder cancer.
Cell Mol Biol (Noisy-le-grand). 2017; 63(9):46-52 [PubMed] Related Publications
To study the role of MMP9 and TIMP2 genotypes and expression in predisposition to bladder cancer and relation with metastasis. 100 urinary bladder cancer patients and 100 healthy controls were included in the study. rs3918242 and rs8179090 genotypes were determined with PCR-RFLP. Quantitative real-time polymerase chain reaction was employed to assess the MMP-9 and TIMP-2 expression in tumors and adjacent healthy tissues. Variant genotype (TT) for rs3918242 polymorphism and rs8179090 variant genotype are not associated with bladder cancer risk. rs3918242 genotype was significantly associated with tumor invasion. In contrast with this, rs8179090 genotype has not shown a significant association with tumor invasion. Both SNPs did not show a significant association with metastatic status. MMP-9 was upregulated in tumors in comparison to cancer free tissues. Significant increase in the expression of MMP-9 was also observed in invasive tumors. TIMP-2 expression was significantly increased in tumors in comparison to cancer free tissues and in metastatic tumors in comparison to non-metastatic tumors. Tissues with rs3918242 variant genotype have shown increased MMP-9 expression.  rs3918242 promoter polymorphism of MMP-9 is significantly associated with tumor invasion, however; there is no positive correlation between TIMP-2 rs8179090 promoter polymorphism variant frequency and invasion. MMP-9 and TIMP-2 genes are upregulated in cancerous tissues when compared to normal bladder tissues.

Rak B, Mehlich D, Garbicz F, et al.
Post-transcriptional Regulation of MMP16 and TIMP2 Expression
Cancer Genomics Proteomics. 2017 Sep-Oct; 14(5):389-401 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: The post-transcriptional regulation of matrix metalloproteinases (MMPs) via microRNAs (miRNAs) has been recently described in numerous human malignancies. However, the exact mechanisms of miRNA-mediated MMPs deregulation in endometrial cancer (EC) remain unclear. Herein, we aimed to analyze the expression of MMP2, MMP16 and TIMP2 and identify miRNAs that modulate their expression.
MATERIALS AND METHODS: Protein expression was assessed by immunohistochemistry in formalin-fixed paraffin-embedded EC samples. Target prediction algorithms were applied to select miRNAs binding the 3'UTRs of MMP16 (miR-377, miR-382, miR-410, miR-200b) or TIMP2 (miR-200b), and their levels were measured by qPCR in laser capture-microdissected tissue fragments. Luciferase assays and western blotting were used to indicate individual miRNA- mRNA interactions.
RESULTS: Overexpression of MMP2 and MMP16 in cancerous tissues corresponded to down-regulation of miR-377, miR-382 and miR-410, while decreased expression of TIMP2 was associated with miR-200b up-regulation. In vitro experiments confirmed direct regulation of MMP16 by miR-382 and miR-410, and TIMP2 by miR-200b in EC Ishikawa cells.
CONCLUSION: We demonstrated novel mechanisms of miRNA-mediated regulation of MMPs activity in EC.

Cheng Y, Geng L, Zhao L, et al.
Human papillomavirus E6-regulated microRNA-20b promotes invasion in cervical cancer by targeting tissue inhibitor of metalloproteinase 2.
Mol Med Rep. 2017; 16(4):5464-5470 [PubMed] Free Access to Full Article Related Publications
Human papillomavirus (HPV) infection alone is not sufficient for development of cervical cancer and further risk factors are involved, however, the underlying mechanism remains to be elucidated. The authors previously used a microarray assay to reveal microR‑20b (miR‑20b) as a key node in the miRNA‑mRNA network of cervical carcinoma. The present study demonstrated an increased expression of miR‑20b in cervical carcinoma tissue. MiR‑20b was regulated by HPV E6 oncoprotein in cervical cancer. Furthermore, miR‑20b overexpression with mimics induced cell morphological alterations and the epithelial‑mesenchymal transition. Treating cervical cancer cells with the miR‑20b inhibitor decreased the migration and invasion of cervical cancer cells. Tissue inhibitor of metalloproteinase 2 (TIMP‑2), a possible antagonist of matrix metalloproteinase 2, is a metastasis suppressor and predicted to be a potential target of miR‑20b. Fluorescence signals were decreased on transducing HeLa cells with a TIMP‑2 3'‑untranslated region plasmid and miR‑20b mimics compared with control. Finally, TIMP‑2 was identified as a novel target of miR‑20b and was demonstrated to be regulated by the HPV oncoprotein. In addition, miR‑20b and TIMP‑2 were involved in cell invasion regulated by HPV E6. The present study demonstrated a novel pathway of HPV/miR‑20b/TIMP‑2 during the process of invasion in cervical cancer cells.

Liu M, An J, Huang M, et al.
MicroRNA-492 overexpression involves in cell proliferation, migration, and radiotherapy response of cervical squamous cell carcinomas.
Mol Carcinog. 2018; 57(1):32-43 [PubMed] Related Publications
MicroRNAs (miRNAs) are small non-coding RNA that target protein-coding mRNAs at the post-transcriptional level. The aim of this study was to define the role of miR-492 in cervical squamous cell carcinomas. After microRNA profiling and comparison, we firstly detected miR-492 expression in 104 tumor tissues biopsies derived from advanced staged (FIGO IIB-IIIB) cervical squamous cell carcinoma patients before receiving concomitant chemoradiotherapy and found miR-492 expression was significantly higher in the specimens that were sensitive to concomitant chemoradiotherapy, as compared with insensitive cancer specimens (P < 0.05). Moreover, higher expression of miR-492 was associated with pelvic lymph node metastasis (LNM) (P < 0.05). Further studies illustrated ectopic miR-492 overexpression in SiHa cells promoted cell proliferation, migration, and enhanced the sensitivity of cervical cancer cells to irradiation by promoting apoptosis. In addition, we identified TIMP2 as a direct miR-492 target, which has been shown to be critical in modulating cancer cell migration and invasion. We also confirmed that miR-492 expression levels in positive pelvic LNM were much higher than negative LNM and miR-492 played a vital role in pelvic lymph node metastasis via regulating miR-492/TIMP2/MMP10 axis. In particular, miR-492 was correlated with prognosis in the subgroup of patients with negative pelvic LNM (P < 0.05) and had a promising value in predicting treatment response in the subgroup of patients with positive pelvic LNM (an AUC of 85%, 75.00% specificity, and 95.24% sensitivity). Taken together, the results suggested that miR-492 may serve as a potential biomarker for cervical cancer treatment and prognosis.

Li X, Zhou Q, Tao L, Yu C
MicroRNA-106a promotes cell migration and invasion by targeting tissue inhibitor of matrix metalloproteinase 2 in cervical cancer.
Oncol Rep. 2017; 38(3):1774-1782 [PubMed] Related Publications
Increasing evidence has demonstrated that miRNAs play a critical role in tumor development and progression. Previous studies have revealed that miR-106a is abnormally expressed in various cancers. However, its function and underlying mechanism in cervical cancer (CC) remains unknown. In this study, we confirmed that the expression of miR-106a was significantly upregulated in both CC cell lines and tissues by qRT-PCR. The increased expression of miR-106a was obviously associated with adverse prognostic features. Moreover, we demonstrated that miR-106a was a novel independent prognostic marker for predicting the 5-year survival of CC patients. The ectopic overexpression of miR‑106a promoted cell migration, invasion and invasion-related gene expression, while downregulated miR-106a reversed the effect. In addition, miR-106a regulated tissue inhibitor of metalloproteinase (TIMP)2 by directly binding to its 3'-UTR, leading to the indution of the expression of matrix metalloproteinases (MMPs). In clinical samples of CC, miR-106a was inversely correlated with TIMP2, which was downregulated in CC. Alteration of TIMP2 expression at least partially abolished the migration, invasion and MMP expression of miR-106a in CC cells. In conclusion, our data indicated that miR-106a promoted the migration, invasion and MMP expression of CC by targeting TIMP2, and may represent a novel potential therapeutic target and prognostic marker for CC.

Yi X, Guo J, Guo J, et al.
EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion.
Sci Rep. 2017; 7(1):3568 [PubMed] Free Access to Full Article Related Publications
Enhancer of zeste homolog 2 (EZH2) is often increased in malignant tumors and is involved in metastasis. EZH2 silences gene expression by tri-methylating the lysine 27 residue of histone H3 (H3K27me3). However, the mechanism underlying EZH2 promotion of ovarian cancer metastasis remains elusive. Here, we showed that EZH2 is up-regulated in ovarian cancer and is associated with tumor metastasis and poor survival by mRNA sequencing and microarray results from databases. Tissue microarray and immunohistochemistry results revealed that EZH2 was negatively correlated with the expression of tissue inhibitor of metalloproteinases 2 (TIMP2). EZH2 overexpression inhibited TIMP2 expression and promoted proteolytic activities of matrix metalloproteinases 2 and 9 and vice versa. EZH2 promoted ovarian cancer invasion and migration, which could be largely reversed by TIMP2 down-regulation in vitro and in vivo. Both H3K27me3 inhibition and demethylation could reduce methylation of the TIMP2 promoter and finally reactivate TIMP2 transcription. The presence of EZH2 and H3K27me3 at the TIMP2 promoter was confirmed by chromatin immunoprecipitation. H3K27me3 and DNA methyltransferases at the promoter were significantly increased by EZH2 overexpression. These results suggest that EZH2 inhibits TIMP2 expression via H3K27me3 and DNA methylation, which relieve the repression of MMP and facilitate ovarian cancer invasion and migration.

Juchniewicz A, Kowalczuk O, Milewski R, et al.
MMP-10, MMP-7, TIMP-1 and TIMP-2 mRNA expression in esophageal cancer.
Acta Biochim Pol. 2017; 64(2):295-299 [PubMed] Related Publications
INTRODUCTION: Tissue inhibitors of metalloproteinases (TIMP) and the matrix metalloproteinases (MMP) are involved in the spread of cancer.
METHODS: We have evaluated the matrix metalloproteinases' (MMP-10, MMP-7) and their inhibitors' (tissue inhibitors of metalloproteinases - TIMP-1, TIMP-2) mRNA expression in 61 esophageal cancer samples from patients who had undergone surgery, by using real-time quantitative RT-PCR, and correlated the results with the patient clinicopathologic features.
RESULTS: MMP-10, MMP-7, TIMP-1, TIMP-2 were overexpressed in 73%, 85%, 55% and 42% of esophageal cancer samples, respectively. The expression of MMP-10, TIMP-1, and TIMP-2 correlated with the tumor size. The MMP-7 overexpression was associated with the tumour stage (I, II vs III, p=0.05) and lymph node metastasis (N0 vs N1, p=0.037).
CONCLUSIONS: We conclude that in the resected esophageal cancer an increased mRNA expression of MMP-7, MMP-10 and TIMP-1 correlated with clinicopathologic features. We suggest that these genes may play a role during progression of the disease.

Wang H, Zhan Y, Jin J, et al.
MicroRNA-15b promotes proliferation and invasion of non‑small cell lung carcinoma cells by directly targeting TIMP2.
Oncol Rep. 2017; 37(6):3305-3312 [PubMed] Related Publications
MicroRNA-15b (miR-15b) plays an important role in tumor development and progression. miR-15b functions differently in various types of malignant tumors. However, the expression pattern and role of miR-15b in non-small cell lung cancer (NSCLC) have not been elucidated. In the present study, we investigated the effect of miR-15b on the occurrence and development of lung cancer and the underlying mechanism. Lung cancer cell lines A549 and LTEP-a-2 were transfected with miR-15b inhibitor or mimic, respectively. Real-time PCR revealed that the expression level of miR-15b was significantly higher in human NSCLC tissues and NSCLC cells, than that of normal tissues and cells, respectively (P<0.05). Moreover, the effect of miR-15b on A549 and LTEP-a-2 cell viability, cell cycle, migration and invasion was further evaluated. Experiments indicated that miR‑15b knockdown inhibited the viability, cell cycle, migration and invasion in A549 cells, while upregulation of miR-15b exhibited the opposite effect. Tissue inhibitor of metallopeptidases 2 (TIMP2) protein and mRNA levels were downregulated after miR-15b overexpression in A549 and LTEP-a-2 cells, respectively. The dual-luciferase reporter gene assay implied that TIMP2 is a direct target gene of miR-15b. Our results indicate that high expression of miR-15b is associated with NSCLC and suggest that miR-15b expression may be a novel biomarker for predicting clinical outcomes in NSCLC patients. The inhibition of miR-15b may even provide helpful therapeutic strategies for the treatment of NSCLC.

Neuhaus J, Schiffer E, Mannello F, et al.
Protease Expression Levels in Prostate Cancer Tissue Can Explain Prostate Cancer-Associated Seminal Biomarkers-An Explorative Concept Study.
Int J Mol Sci. 2017; 18(5) [PubMed] Free Access to Full Article Related Publications
Previously, we described prostate cancer (PCa) detection (83% sensitivity; 67% specificity) in seminal plasma by CE-MS/MS. Moreover, advanced disease was distinguished from organ-confined tumors with 80% sensitivity and 82% specificity. The discovered biomarkers were naturally occurring fragments of larger seminal proteins, predominantly semenogelin 1 and 2, representing endpoints of the ejaculate liquefaction. Here we identified proteases putatively involved in PCa specific protein cleavage, and examined gene expression and tissue protein levels, jointly with cell localization in normal prostate (nP), benign prostate hyperplasia (BPH), seminal vesicles and PCa using qPCR, Western blotting and confocal laser scanning microscopy. We found differential gene expression of chymase (CMA1), matrix metalloproteinases (MMP3, MMP7), and upregulation of MMP14 and tissue inhibitors (TIMP1 and TIMP2) in BPH. In contrast tissue protein levels of MMP14 were downregulated in PCa. MMP3/TIMP1 and MMP7/TIMP1 ratios were decreased in BPH. In seminal vesicles, we found low-level expression of most proteases and, interestingly, we also detected TIMP1 and low levels of TIMP2. We conclude that MMP3 and MMP7 activity is different in PCa compared to BPH due to fine regulation by their inhibitor TIMP1. Our findings support the concept of seminal plasma biomarkers as non-invasive tool for PCa detection and risk stratification.

Shih YL, Chou HM, Chou HC, et al.
Casticin impairs cell migration and invasion of mouse melanoma B16F10 cells via PI3K/AKT and NF-κB signaling pathways.
Environ Toxicol. 2017; 32(9):2097-2112 [PubMed] Related Publications
Casticin, a polymethoxyflavone, is one of the major active components obtained from Fructus viticis, which have been shown to have anticancer activities including induce cell apoptosis in human cancer cells. The aim of this study was to investigate the molecular mechanisms by which casticin inhibits cell migration and invasion of mouse melanoma B16F10 cells. Cell viability was examined by MTT assay and the results indicated that casticin decreased the total percentages of viable cells in dose-dependent manners. Casticin affected cell migration and invasion in B16F10 cells were examined by wound healing mobility assay and Boyden chamber migration and invasion assay and results indicated that casticin inhibited cell migration and invasion in dose-dependent manners. Western blotting was used to examine the protein expression of B16F10 cells after exposed to casticin and the results showed that casticin decreased the expressions of MMP-9, MMP-2, MMP-1, FAK, 14-3-3, GRB2, Akt, NF-κB p65, SOS-1, p-EGFR, p-JNK 1/2, uPA, and Rho A in B16F10 cells. Furthermore, cDNA microarray assay was used to show that casticin affected associated gene expression of cell migration and invasion and the results indicated that casticin affected some of the gene expression such as increased SCN1B (cell adhesion molecule 1) and TIMP2 (TIMP metallopeptidase inhibitor 2) and decreased NDUFS4 (NADH dehydrogenase (ubiquinone) Fe-S protein4), VEGFA (vascular endothelial growth factor A), and DDIT3 (DNA-damage-inducible transcript 3) which associated cell migration and invasion in B16F10 cells. Based on those observations, we suggest that casticin could be used as a novel anticancer metastasis of melanoma cancer in the future.

Fang F, Song T, Zhang T, et al.
MiR-425-5p promotes invasion and metastasis of hepatocellular carcinoma cells through SCAI-mediated dysregulation of multiple signaling pathways.
Oncotarget. 2017; 8(19):31745-31757 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) play critical roles in hepatocellular carcinoma (HCC) progression and are key determinants of prognosis. In this study, we found that miR-425-5p was elevated in HCC and correlated with poor prognostic clinicopathological features and low post-operative long-term survival. Multivariate survival analysis indicated that miR-425-5p expression was an independent risk factor for overall and disease-free survival. Interestingly, miR-425-5p promoted invasion and metastasis by HCC cells, but not HCC cell proliferation or apoptosis in vitro. SCAI and PTEN were determined to be downstream targets of miR-425-5p. miR-425-5p-mediated effects were inhibited by ectopic expression of SCAI, and PTEN exhibited a smaller inhibitory effect. SCAI also suppressed PTEN expression. In addition, miR-425-5p promoted epithelial-to-mesenchymal transition (EMT), which was antagonized by SCAI. miR-425-5p also promoted HCC cell invasion and metastasis via SCAI-mediated dysregulation of integrin β1-Fak/Src-RhoA/CDC42, PTEN-AKT, and TIMP2-MMP2/MMP9 signaling. Finally, miR-425-5p promoted metastasis in a xenograft mouse model of HCC. These results indicate that miR-425-5p facilitates EMT and extracellular matrix degradation and promotes HCC metastasis through SCAI-mediated dysregulation of multiple signaling pathways. MiR-425-5p is therefore a potential prognostic biomarker and novel therapeutic target in HCC.

Bose KS, Sarma RH
Delineation of the intimate details of the backbone conformation of pyridine nucleotide coenzymes in aqueous solution.
Biochem Biophys Res Commun. 1975; 66(4):1173-9 [PubMed] Related Publications

Bose KS, Sarma RH
Delineation of the intimate details of the backbone conformation of pyridine nucleotide coenzymes in aqueous solution.
Biochem Biophys Res Commun. 1975; 66(4):1173-9 [PubMed] Related Publications

Moroi K, Sato T
Comparison between procaine and isocarboxazid metabolism in vitro by a liver microsomal amidase-esterase.
Biochem Pharmacol. 1975; 24(16):1517-21 [PubMed] Related Publications

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