Gene Summary

Gene:TIMP3; TIMP metallopeptidase inhibitor 3
Aliases: SFD, K222, K222TA2, HSMRK222
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:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:metalloproteinase inhibitor 3
Source:NCBIAccessed: 29 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 29 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (9)

Latest Publications: TIMP3 (cancer-related)

Echevarria MI, Awasthi S, Cheng CH, et al.
African American Specific Gene Panel Predictive of Poor Prostate Cancer Outcome.
J Urol. 2019; 202(2):247-255 [PubMed] Related Publications
PURPOSE: Most prostate cancer in African American men lacks the ETS (E26 transforming specific) family fusion event (ETS-). We aimed to establish clinically relevant biomarkers in African American men by studying ETS dependent gene expression patterns to identified race specific genes predictive of outcomes.
MATERIALS AND METHODS: Two multicenter cohorts of a total of 1,427 men were used for the discovery and validation (635 and 792 men, respectively) of race specific predictive biomarkers. We used false discovery rate adjusted q values to identify race and ETS dependent genes which were differentially expressed in African American men who experienced biochemical recurrence within 5 years. Principal component modeling along with survival analysis was done to assess the accuracy of the gene panel in predicting recurrence.
RESULTS: We identified 3,047 genes which were differentially expressed based on ETS status. Of these genes 362 were differentially expressed in a race specific manner (false discovery rate 0.025 or less). A total of 81 genes were race specific and over expressed in African American men who experienced biochemical recurrence. The final gene panel included APOD, BCL6, EMP1, MYADM, SRGN and TIMP3. These genes were associated with 5-year biochemical recurrence (HR 1.97, 95% CI 1.27-3.06, p = 0.002) and they improved the predictive accuracy of clinicopathological variables only in African American men (60-month time dependent AUC 0.72).
CONCLUSIONS: In an effort to elucidate biological features associated with prostate cancer aggressiveness in African American men we identified ETS dependent biomarkers predicting early onset biochemical recurrence only in African American men. Thus, these ETS dependent biomarkers representing ideal candidates for biomarkers of aggressive disease in this patient population.

Kubatka P, Uramova S, Kello M, et al.
Anticancer Activities of
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
Naturally-occurring mixtures of phytochemicals present in plant foods are proposed to possess tumor-suppressive activities. In this work, we aimed to evaluate the antitumor effects of

Zhang X, Yang P, Luo X, et al.
High olive oil diets enhance cervical tumour growth in mice: transcriptome analysis for potential candidate genes and pathways.
Lipids Health Dis. 2019; 18(1):76 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Numerous epidemiologic studies have found a close association between obesity and cancer. Dietary fat is a fundamental contributor to obesity and is a risk factor for cancer. Thus far, the impact of dietary olive oil on cancer development remains inconclusive, and little is known about its underlying mechanisms.
METHODS: Nude mouse xenograft models were used to examine the effects of high olive oil diet feeding on cervical cancer (CC) development and progression. Cell proliferation, migration and invasion were observed by the methods of EdU incorporation, Wound healing and Transwell assay, separately. RNA-sequencing technology and comprehensive bioinformatics analyses were used to elucidate the molecular processes regulated by dietary fat. Differentially expressed genes (DEGs) were identified and were functionally analyzed by Gene Ontology (GO), Kyoto Enrichment of Genes and Genomes (KEGG). Then, protein-protein interaction (PPI) network and sub-PPI network analyses were conducted using the STRING database and Cytoscape software.
RESULTS: A high olive oil diet aggravated tumourigenesis in an experimental xenograft model of CC. Oleic acid, the main ingredient of olive oil, promoted cell growth and migration in vitro. Transcriptome sequencing analysis of xenograft tumour tissues was then performed to elucidate the regulation of molecular events regulated by dietary fat. Dietary olive oil induced 648 DEGs, comprising 155 up-regulated DEGs and 493 down-regulated DEGs. GO and pathway enrichment analysis revealed that some of the DEGs including EGR1 and FOXN2 were involved in the transcription regulation and others, including TGFB2 and COL4A3 in cell proliferation. The 15 most strongly associated DEGs were selected from the PPI network and hub genes including JUN, TIMP3, OAS1, OASL and EGR1 were confirmed by real-time quantitative PCR analysis.
CONCLUSIONS: Our study suggests that a high olive oil diet aggravates CC progression in vivo and in vitro. We provide clues to build a potential link between dietary fat and cancerogenesis and identify areas requiring further investigation.

Prawdzic Seńkowska A, Kiczmer P, Strzelczyk JK, et al.
Impact of HPV infection on gene expression and methylation in oral cancer patients.
J Med Microbiol. 2019; 68(3):440-445 [PubMed] Related Publications
PURPOSE: The current study aimed to examine the association between head and neck squamous cell carcinoma (HNSCC) and infection with different human papillomavirus virus (HPV) subtypes, including analysis of promoter methylation of several genes (APC, CDKN2A, MGMT, CDH1 and TIMP3) and the correlation with their mRNA expression in tumours and surgical margins.
METHODOLOGY: In 47 patients with a primary tumour of the oral cavity, HPV detection and identification of 33 subtypes was performed after previous DNA isolation using a GenoFlow HPV Array Test Kit.
RESULTS: Fifteen patients (31.92 %) were HPV [+] and the following HPV types were detected: 16 (46.67 %), 18 (6.67 %) and 43/44 (40 %). This study is the first to describe HPV 43/44 subtypes in HNSCC in a Polish population. We noted no clinical significance of HPV [+] HNSCC compared to HPV [-], however, this differed among HPV subtypes. CDKN2A promoter methylation was more frequent in HPV-16/18 patients compared to HPV43/44 patients, but there was no difference in gene expression level between HPV [+] and [-] patients.
CONCLUSION: We detected HPV infection in 31.92 % of oral cancer cases. HPV 16, along with HPV 43/44, were the most frequent subtypes. Knowledge of HPV [+] HNSCC biology may be useful in establishing the prognosis and developing novel therapies in future.

Smal MP, Kuzhir TD, Savina NV, et al.
BER gene polymorphisms associated with key molecular events in bladder cancer.
Exp Oncol. 2018; 40(4):288-298 [PubMed] Related Publications
AIM: Base excision repair (BER) gene polymorphisms are known to play an independent role in predisposition to developing different cancers as well as to be associated with clinicopathological traits of the disease modifying its clinical outcomes. One of the underlying mechanisms is presumed to include interplay between BER gene polymorphisms and key mutational, epigenetic and chromosomal events in tumor tissues. The present study was aimed at elucidating potential gene-gene interaction and assessing their mutual effects in bladder cancer (BC).
MATERIALS AND METHODS: The earlier obtained data on genotyping patients with verified diagnosis of BC for OGG1 rs1052133 (Ser326Cys) and XRCC1 rs25487 (Arg399Gln) polymorphisms were used for this study. The tumor tissue samples from the same patients were analyzed for mutations, epigenetic variations and losses of heterozygosity in some key genes involved in divergent pathogenic pathways of BC.
RESULTS: It was shown that the OGG1 (326 codon) heterozygous genotype as well as the minor 326Cys allele can intensify a mutational response of the RAS locus in urothelial carcinomas in the total cohort of patients simultaneously decreasing the mutation rates in the PIK3CA locus in smokers. The XRCC1 (399 codon) heterozygous genotype as well as the minor 399Gln allele reduced the frequency of LOH in the PTEN and TNKS genes, but did not affect the mutational variability in any locus tested. Both polymorphisms influenced the methylation status, carriers of OGG1 326Ser/Cys or Ser/Cys+Cys/Cys genotypes demonstrating increased frequency of methylated RUNX3 and ISL1 genes whereas the similar effect of XRCC1 polymorphism concerning methylation of p16 and TIMP3 genes. When dividing the total cohort into groups based on the extent of tumor spread, the observed associations were characteristic of non-muscle invasive BC.
CONCLUSION: The BER gene polymorphisms contributed to modification of key molecular events in urothelial carcinomas. Their mutual effects mainly manifested in non-muscle invasive BC. The underlying mechanisms as well as possible clinical outcomes need to be further explored to propose novel prognostic biomarkers for BC.

Wanga XZ, Gu JL, Gao M, et al.
Peperomin E Induces Promoter Hypomethylation of Metastatic-Suppressor Genes and Attenuates Metastasis in Poorly Differentiated Gastric Cancer.
Cell Physiol Biochem. 2018; 50(6):2341-2364 [PubMed] Related Publications
BACKGROUND/AIMS: Peperomin E (PepE), a natural secolignan isolated from the whole plant of Peperomia dindygulensis, has been reported by ourselves and others to display potent anti-cancer effects in many types cancer cells, especially gastric cancer. However, the effects of PepE on the metastasis of poorly-differentiated gastric cancer cells and the underlying molecular mechanisms have not been well elucidated.
METHODS: We evaluated PepE effects on gastric cancer cell invasion and migration in vitro via wound healing and transwell assays and those on growth and metastasis in vivo using an orthotopic xenograft NOD-SCID mouse model. DNA methyltransferase (DNMT) activity was determined using a colorimetric DNMT activity/inhibition assay kit. PepE binding kinetics to DNMTs were determined using the bio-layer interferometry binding assay. Gene and protein levels of DNMTs, AMPKα-Sp1 signaling molecules, and metastatic-suppressor genes in PepE-treated gastric cancer cells were determined using quantitative reverse transcription-PCR arrays and western blotting. The effect of PepE on Sp1 binding to the DNMT promoter was determined by electrophoretic mobility-shift assay. Global DNA methylation levels were determined using liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The methylation status of silenced metastatic-suppressor genes (MSGs) in gastric cancer cells was investigated by methylation-specific PCR.
RESULTS: PepE can dose-dependently suppress invasion and migration of poorly-differentiated gastric cancer cells in vitro and in vivo with low toxicity against normal cells. Mechanistically, PepE not only covalently binds to the catalytic domain of DNMT1 and inhibits its activity (IC50 value 3.61 μM) but also down-regulates DNMT1, 3a, and 3b mRNA and protein expression in in gastric cancer cells, by disruption of the physical interaction of Sp1 with the DNMT1, 3a, and 3b promoter and mediation of the AMPKα-Sp1 signaling pathway. The dual inhibition activity of PepE toward DNMTs renders a relative global DNA hypomethylation, which induces MSG promoter hypomethylation (e.g., E-cadherin and TIMP3) and enhances their expression in gastric cancer cells.
CONCLUSION: Collectively, our data indicated that PepE may represent a promising therapeutic lead compound for intervention in gastric cancer metastasis and may also exhibit potential as a DNA methylation inhibitor for use in epigenetic cancer therapy.

Jones RA, Franks SE, Moorehead RA
Comparative mRNA and miRNA transcriptome analysis of a mouse model of IGFIR-driven lung cancer.
PLoS One. 2018; 13(11):e0206948 [PubMed] Free Access to Full Article Related Publications
Mouse models of cancer play an important role in elucidating the molecular mechanisms that contribute to tumorigenesis. The extent to which these models resemble one another and their human counterparts at the molecular level is critical in understanding tumorigenesis. In this study, we carried out a comparative gene expression analysis to generate a detailed molecular portrait of a transgenic mouse model of IGFIR-driven lung cancer. IGFIR-driven tumors displayed a strong resemblance with established mouse models of lung adenocarcinoma, particularly EGFR-driven models highlighted by elevated levels of the EGFR ligands Ereg and Areg. Cross-species analysis revealed a shared increase in human lung adenocarcinoma markers including Nkx2.1 and Napsa as well as alterations in a subset of genes with oncogenic and tumor suppressive properties such as Aurka, Ret, Klf4 and Lats2. Integrated miRNA and mRNA analysis in IGFIR-driven tumors identified interaction pairs with roles in ErbB signaling while cross-species analysis revealed coordinated expression of a subset of conserved miRNAs and their targets including miR-21-5p (Reck, Timp3 and Tgfbr3). Overall, these findings support the use of SPC-IGFIR mice as a model of human lung adenocarcinoma and provide a comprehensive knowledge base to dissect the molecular pathogenesis of tumor initiation and progression.

Xerri L, Adélaïde J, Avenin M, et al.
Common origin of sequential cutaneous CD30+ lymphoproliferations with nodal involvement evidenced by genome-wide clonal evolution.
Histopathology. 2019; 74(4):654-662 [PubMed] Related Publications
AIMS: This study sought to clarify the molecular pathways underlying the putative evolution from lymphomatoid papulosis (LyP) to cutaneous anaplastic large-cell lymphoma (c-ALCL) and lymph node invasion (LNI).
METHODS AND RESULTS: We analysed nine sequential tumours from the same patient presenting with parallel evolution of LyP (n = 3) and c-ALCL (n = 1) with LNI (n = 1), combined with systemic diffuse large B-cell lymphoma (DLBCL) (n = 4). Clonality analysis showed a common clonal T-cell origin in the five CD30+ lesions, and a common clonal B-cell origin in the four DLBCL relapses. Array-comparative genomic hybridisation and targeted next-generation sequencing analysis demonstrated relative genomic stability of LyP lesions as compared with clonally related anaplastic large-cell lymphoma (ALCL) tumours, which showed 4q and 22q13 deletions involving the PRDM8 and TIMP3 tumour suppressor genes, respectively. The three analysed CD30+ lesions showed mostly private (specific to each sample) genetic alterations, suggesting early divergence from a common precursor. In contrast, DLBCL tumours showed progressive accumulation of private alterations, indicating late divergence.
CONCLUSIONS: Sequential cutaneous and nodal CD30+ tumours were clonally related. This suggests that LyP, c-ALCL and LNI represent a continuous spectrum of clonal evolution emerging from a common precursor of cutaneous CD30+ lymphoproliferations. Therefore, nodal ALCL tumours in the context of LyP should be considered as a form of transformation rather than composite lymphoma.

Zhang B, Wang L, Zhao X, et al.
Identification of Candidate Genes Associated with Chemotherapy Resistance in Ovarian Cancer.
Ann Clin Lab Sci. 2018; 48(5):573-579 [PubMed] Related Publications
Ovarian cancer is the leading cause of death due to malignant tumors in female reproductive organs. However, the lack of understanding regarding its pathogenesis brings difficulties to study it. In this study, we analyze the differently expressed genes in both GSE54388 (ovarian cancer vs. normal ovarian tissues) and GSE51373 (chemotherapy-resistant vs. chemotherapy-sensitive tissues). By intersecting the differently expressed genes, 79 genes were identified. Then, further function enrichment analysis, including GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis, was performed. Also, a protein-protein network analysis was conducted to reveal the potential relationship between genes. Finally, survival analysis was utilized to find out that FOXL2 (Forkhead Box L2), TIMP3 (TIMP Metallopeptidase Inhibitor 3), and ZEB1 (Zinc Finger E-Box Binding Homeobox 1) may serve as biomarkers for predicting the prognosis of ovarian cancer patients.

Yuniarti L, Mustofa M, Aryandono T, Haryana SM
Synergistic Action of 1,2-Epoxy-3 (3- (3,4-dimethoxyphenyl)- 4H-1-benzopiyran-4-on) Propane with Doxorubicin and Cisplatin through Increasing of p53, TIMP-3, and MicroRNA-34a in Cervical Cancer Cell Line (HeLa)
Asian Pac J Cancer Prev. 2018; 19(10):2955-2962 [PubMed] Free Access to Full Article Related Publications
Objective: Cervical cancer is the second most common cancer among women worldwide, with a high mortality rate especially in developing countries. Insufficient treatment for cervical cancer, multiple side effects, and high drug prices encourage researchers to look for effective and selective cancer drugs with appropriate molecular targets. This study explored the cytotoxicity of (1,2-epoxy-3(3-(3,4-dimethoxyphenyl)-4H-1-benzopyran-4-on) propane (EPI) synthesized from clove leaves oil on HeLa cells, its combination with doxorubicin (DOX) and cisplatin (CIS), and also their influence on p53, TIMP-3, and miR-34a as therapeutic targets. Materials and Methods: This research was an experimental in vitro study on cervical cancer uteri culture. The cytotoxicity was analyzed by MTT assay. The drug combination synergisms were indicated by the combination index (CI) (using CompuSyn 1.4). HeLa cells in 32 wells were divided into eight groups as negative control, which were given EPI ½IC50, EPI IC50, EPI 2IC50, DOX IC50, combination of EPI+DOX, CIS, and the combination of EPI+CIS. The p53 and TIMP-3 concentrations were measured using ELISA, and expressions of miR-34a with qRT-PCR. One-way ANOVA and post hoc Tukey tests were performed to determine the mean difference of all variables between the study groups. Results: IC50 for EPI was 33.24 (±3.01) μg/ml, while DOX and CIS were 4.8 μg/ml (±0.1), and 23.34 μg/ml (±3.01), respectively, while CI values for EPI-DOX were <0.1 and for EPI-CIS <0.9. Expression of p53 in group 6 (1.67±0.31) μg/ml and 8 (1.18±0.18) μg/ml, TIMP-3 6 (3.81±0.49) μg/ml and 8 (2.93±0.42) μg/ml were significantly higher compared to the control group (p<0.05). All treatment groups showed significantly increased miR-34a expressions compared to the control group (p<0.05). Conclusion: The combinations showed a very strong synergism and a moderate slight synergism for EPI-DOX and EPI-CIS. Both combinations were able to increase the expressions of p53, TIMP-3 proteins, and MiR-34a in the HeLa cells.

Liu X, Cao M, Palomares M, et al.
Metastatic breast cancer cells overexpress and secrete miR-218 to regulate type I collagen deposition by osteoblasts.
Breast Cancer Res. 2018; 20(1):127 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Bone is one of the most frequent metastatic sites of advanced breast cancer. Current therapeutic agents aim to inhibit osteoclast-mediated bone resorption but only have palliative effects. During normal bone remodeling, the balance between bone resorption and osteoblast-mediated bone formation is essential for bone homeostasis. One major function of osteoblast during bone formation is to secrete type I procollagen, which will then be processed before being crosslinked and deposited into the bone matrix.
METHODS: Small RNA sequencing and quantitative real-time PCR were used to detect miRNA levels in patient blood samples and in the cell lysates as well as extracellular vesicles of parental and bone-tropic MDA-MB-231 breast cancer cells. The effects of cancer cell-derived extracellular vesicles isolated by ultracentrifugation and carrying varying levels of miR-218 were examined in osteoblasts by quantitative real-time PCR, Western blot analysis, and P1NP bone formation marker analysis. Cancer cells overexpressing miR-218 were examined by transcriptome profiling through RNA sequencing to identify intrinsic genes and pathways influenced by miR-218.
RESULTS: We show that circulating miR-218 is associated with breast cancer bone metastasis. Cancer-secreted miR-218 directly downregulates type I collagen in osteoblasts, whereas intracellular miR-218 in breast cancer cells regulates the expression of inhibin β subunits. Increased cancer secretion of inhibin βA results in elevated Timp3 expression in osteoblasts and the subsequent repression of procollagen processing during osteoblast differentiation.
CONCLUSIONS: Here we identify a twofold function of cancer-derived miR-218, whose levels in the blood are associated with breast cancer metastasis to the bone, in the regulation of type I collagen deposition by osteoblasts. The adaptation of the bone niche mediated by miR-218 might further tilt the balance towards osteolysis, thereby facilitating other mechanisms to promote bone metastasis.

Boussadia Z, Lamberti J, Mattei F, et al.
Acidic microenvironment plays a key role in human melanoma progression through a sustained exosome mediated transfer of clinically relevant metastatic molecules.
J Exp Clin Cancer Res. 2018; 37(1):245 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Microenvironment cues involved in melanoma progression are largely unknown. Melanoma is highly influenced in its aggressive phenotype by the changes it determinates in its microenvironment, such as pH decrease, in turn influencing cancer cell invasiveness, progression and tissue remodelling through an abundant secretion of exosomes, dictating cancer strategy to the whole host. A role of exosomes in driving melanoma progression under microenvironmental acidity was never described.
METHODS: We studied four differently staged human melanoma lines, reflecting melanoma progression, under microenvironmental acidic pHs pressure ranging between pH 6.0-6.7. To estimate exosome secretion as a function of tumor stage and environmental pH, we applied a technique to generate native fluorescent exosomes characterized by vesicles integrity, size, density, markers expression, and quantifiable by direct FACS analysis. Functional roles of exosomes were tested in migration and invasion tests. Then we performed a comparative proteomic analysis of acid versus control exosomes to elucidate a specific signature involved in melanoma progression.
RESULTS: We found that metastatic melanoma secretes a higher exosome amount than primary melanoma, and that acidic pH increases exosome secretion when melanoma is in an intermediate stage, i.e. metastatic non-invasive. We were thus able to show that acidic pH influences the intercellular cross-talk mediated by exosomes. In fact when exposed to exosomes produced in an acidic medium, pH naïve melanoma cells acquire migratory and invasive capacities likely due to transfer of metastatic exosomal proteins, favoring cell motility and angiogenesis. A Prognoscan-based meta-analysis study of proteins enriched in acidic exosomes, identified 11 genes (HRAS, GANAB, CFL2, HSP90B1, HSP90AB1, GSN, HSPA1L, NRAS, HSPA5, TIMP3, HYOU1), significantly correlating with poor prognosis, whose high expression was in part confirmed in bioptic samples of lymph node metastases.
CONCLUSIONS: A crucial step of melanoma progression does occur at melanoma intermediate -stage, when extracellular acidic pH induces an abundant release and intra-tumoral uptake of exosomes. Such exosomes are endowed with pro-invasive molecules of clinical relevance, which may provide a signature of melanoma advancement.

Moses-Fynn E, Tang W, Beyene D, et al.
Correlating blood-based DNA methylation markers and prostate cancer risk in African-American men.
PLoS One. 2018; 13(9):e0203322 [PubMed] Free Access to Full Article Related Publications
The objective of this work was to investigate the clinical significance of promoter gene DNA methylation changes in whole blood from African-American (AA) men with prostate cancer (PCa). We used high throughput pyrosequencing analysis to quantify percentage DNA methylation levels in a panel of 8 genes (RARβ2, TIMP3, SPARC, CDH13, HIN1, LINE1, CYB5R2 and DRD2) in blood DNA obtained from PCa and non-cancerous controls cases. Correlations of methylation status and various clinicopathological features were evaluated. Six genes tested achieved significant difference in DNA methylation levels between the PCa compared to control cases (P < 0.05). The TIMP3 loci demonstrated significant correlation of DNA methylation with age for all cases analyzed (p < 0.05). We observed an inverse correlation between CDH13 methylation (p = 0.045; r = -0.21) and serum vitamin D level whereas TIMP3 methylation (p = 0.021; r = -0.24) and DRD2 methylation (p = 0.056; r = -0.201) showed inverse correlation with supplementary vitamin D in the cancer cases. We also observed a direct correlation between methylation of RARβ2 (p = 0.0036; r = 0.293) and SPARC (p = 0.0134; r = 0.20) loci with PSA level in the controls but not the cancer cases. In addition, alcohol cases significantly correlated with higher RARβ2 methylation (p = 0.0314) in comparison with non-alcohol cases. Furthermore, we observed an inverse correlation of DRD2 methylation (p = 0.0349; r = -0.343) and Gleason score. Our data suggests that promoter methylation occurred more frequently in the blood of AA PCa and is associated with various clinicopathological features in AA men with PCa.

Inoue M, Uchida Y, Edagawa M, et al.
The stress response gene ATF3 is a direct target of the Wnt/β-catenin pathway and inhibits the invasion and migration of HCT116 human colorectal cancer cells.
PLoS One. 2018; 13(7):e0194160 [PubMed] Free Access to Full Article Related Publications
Aberrant Wnt/β-catenin signaling is implicated in tumorigenesis and the progression of human colorectal cancers, and mutations in the components of the Wnt/β-catenin signaling pathway are observed in the majority of patients. Therefore, extensive studies on the Wnt signaling pathway and its target genes are crucial to understand the molecular events of tumorigenesis and develop an efficacious therapy. In this study, we showed that the stress response gene ATF3 is transcriptionally activated by the binding of β-catenin and TCF4 to the redundant TCF4 site at the proximal promoter region of the ATF3 gene, indicating that ATF3 is a direct target of the Wnt/β-catenin pathway. The loss of function or overexpression studies showed that ATF3 inhibited the migration or invasion of HCT116 cells. The expression of some MMP and TIMP genes and the ratio of MMP2/9 to TIMP3/4 mRNAs was differentially regulated by ATF3. Therefore, though ATF3 is activated downstream of the Wnt/β-catenin pathway, it acts as a negative regulator of the migration and invasion of HCT116 human colon cancer cells exhibiting aberrant Wnt/β-catenin activity. ATF3 is a candidate biomarker and target for human colorectal cancer treatment and prevention.

Li W, Yi J, Zheng X, et al.
miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway.
Clin Epigenetics. 2018; 10:64 [PubMed] Free Access to Full Article Related Publications
Background: miR-29c has been associated with the progression of many cancers. However, the function and mechanism of miR-29c have not been well investigated in breast cancers.
Methods: Real-time quantitative PCR was used to assess expression of miR-29c and DNMT3B mRNA. Western blot and immunochemistry were used to examine the expression of DNA methyltransferase 3B (DNMT3B) protein in breast cancer cells and tissues. The functional roles of miR-29c in breast cancer cells such as proliferation, migration, invasion, colony formation, and 3D growth were evaluated using MTT, transwell chambers, soft agar, and 3D Matrigel culture, respectively. In addition, the luciferase reporter assay was used to check if miR-29c binds the 3'UTR of DNMT3B. The effects of miR-29c on the DNMT3B/TIMP3/STAT1/FOXO1 pathway were also examined using Western blot and methyl-specific qPCR. The specific inhibitor of STAT1, fludarabine, was used to further check the mechanism of miR-29c function in breast cancer cells. Studies on cell functions were carried out in DNMT3B siRNA cell lines.
Results: The expression of miR-29c was decreased with the progression of breast cancers and was closely associated with an overall survival rate of patients. Overexpression of miR-29c inhibited the proliferation, migration, invasion, colony formation, and growth in 3D Matrigel while knockdown of miR-29c promoted these processes in breast cancer cells. In addition, miR-29c was found to bind 3'UTR of DNMT3B and inhibits the expression of DNMT3B, which was elevated in breast cancers. Moreover, the protein level of TIMP3 was reduced whereas methylation of TIMP3 was increased in miR-29c knockdown cells compared to control. On the contrary, the protein level of TIMP3 was increased whereas methylation of TIMP3 was reduced in miR-29c-overexpressing cells compared to control. Knockdown of DNMT3B reduced the proliferation, migration, and invasion of breast cancer cell lines. Finally, our results showed that miR-29c exerted its function in breast cancers by regulating the TIMP3/STAT1/FOXO1 pathway.
Conclusion: The results suggest that miR-29c plays a significant role in suppressing the progression of breast cancers and that miR-29c may be used as a biomarker of breast cancers.

Strzelczyk JK, Krakowczyk Ł, Gołąbek K, Owczarek AJ
Expression profiles of selected genes in tumors and matched surgical margins in oral cavity cancer: Do we have to pay attention to the molecular analysis of the surgical margins?
Adv Clin Exp Med. 2018; 27(6):833-840 [PubMed] Related Publications
BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are associated with an interplay between genetics and the environment; they account for 3% of all diagnosed malignant tumors in men and 2% of those in women.
OBJECTIVES: The aim of the study was to analyze the significance of TIMP3, SFRP1, SFRP2, CDH1, RASSF1, RORA, and DAPK1 gene expression in head and neck squamous cell carcinoma tumors, and in matching surgical margin samples. We also analyzed the association between clinical parameters and the expression of the selected genes.
MATERIAL AND METHODS: Following surgical resection, 56 primary HNSCC tumors and matching surgical margin samples were collected from patients at the Clinic of Oncological and Reconstructive Surgery of Maria Skłodowska-Curie Memorial Cancer Center and the Institute of Oncology in Gliwice, Poland. The gene expression levels were analyzed by quantitative reverse transcription (qRT)-PCR.
RESULTS: SFRP1 gene expression was statistically significantly lower in the tumor samples than in the surgical margins (0.30 ±0.36 vs 0.62 ±0.36; p < 0.01). No correlation was found between gene expression and clinical parameters, except DAPK1, where low expression correlated with alcohol abuse (0.85 ±1.19 vs 1.97 ±3.22; p = 0.074). Moreover, patients with G3 grade tumors, i.e., poorly differentiated tumors, had significantly higher values of DAPK1 gene expression than the G1 (well-differentiated tumors) and G2 (moderately differentiated) groups.
CONCLUSIONS: There are many different reasons and concepts for altered gene expression in tumors and surgical margin tissue. Tumor heterogeneity and its microenvironment are undoubtedly linked to the biology of HNSCC. In order to understand specific tumor behavior and the microenvironment, further studies are needed. To find markers connected with cancer development and to provide insight into the earliest stages of cancer development, attention should also be focused on molecular analysis of the surgical margins.

Wang X, Shi Z, Liu X, et al.
Upregulation of miR-191 promotes cell growth and invasion via targeting TIMP3 in prostate cancer.
J BUON. 2018 Mar-Apr; 23(2):444-452 [PubMed] Related Publications
PURPOSE: Prostate cancer (PCa) is the most frequently malignant neoplasm in men. MicroRNAs (miRs) have been identified to play important biological roles in a variety of tumors. Several studies showed that miR-191 was involved in the development of different cancers, but its role in prostate cancer remains unclear.
METHODS: Human PCa cell lines DU145, PC-3 and LNCAP, and benign prostate hyperplasia (BPH) and human prostate epithelial cell line RWPE-1 were used. The expression level of miR-191 in 48 paired prostate tumor and adjacent normal tissues was assessed along with the clinical patient features. Synthetic miR-191 mimics and inhibitors were used to overexpress or inhibit the miR-191 level. CCK8 and colony formation assay were used to evaluate the cell growth. The ability of cell invasion was studied by transwell assay. Dual-luciferase experiment was used to identify the target gene and western blot was performed to evaluate the protein level.
RESULTS: miR-191 was overexpressed in PCa tissue samples compared to the normal group as well in PCa-derived cell lines. Upregulation miR-191 in PC-3 cells significantly promoted while downregulation miR-191 in DU145 cells retarded the cell proliferation and invasion. Furthermore, TIMP3 were proved to be a direct target gene of miR-191 and knockdown of TIMP3 reversed the function of miR-191 downregulation.
CONCLUSION: This study demonstrated that miR-191 promoted the cell growth and invasion ability in prostate cancer through downregulating TIMP3 and might be a potential target for the biotherapy for PCa.

Maleva Kostovska I, Jakimovska M, Popovska-Jankovic K, et al.
TIMP3 Promoter Methylation Represents an Epigenetic Marker of BRCA1ness Breast Cancer Tumours.
Pathol Oncol Res. 2018; 24(4):937-940 [PubMed] Related Publications
Tumours presenting BRCAness profile behave more aggressively and are more invasive as a consequence of their complex genetic and epigenetic alterations, caused by impaired fidelity of the DNA repair processes. Methylation of promoter CpG islands represents an alternative mechanism to inactivate DNA repair and tumour suppressor genes. In our study, we analyzed the frequency of methylation changes of 24 tumour suppressor genes and explored their association with BRCAness profile. BRCA1ness profile and aberrant methylation were studied in 233 fresh frozen breast tumour tissues by Multiplex Ligation-dependent Probe Amplification (MLPA) and Methylation Specific (MS)-MLPA methods, respectively. Our analyses revealed that 12.4% of the breast cancer (BC) patients had tumours with a BRCA1ness profile. TIMP3 showed significantly higher (p = 5.8х10

Shen X, Gao X, Li H, et al.
TIMP-3 Increases the Chemosensitivity of Laryngeal Carcinoma to Cisplatin via Facilitating Mitochondria-Dependent Apoptosis.
Oncol Res. 2018; 27(1):73-80 [PubMed] Related Publications
Laryngeal carcinoma is a type of head and neck carcinoma with a high incidence and mortality. Chemotherapy treatments of human laryngeal carcinoma may fail due to the development of chemoresistance. Tissue inhibitor of metalloproteinase 3 (TIMP-3) has been shown to be implicated in a number of pathological processes typical for cancer. The present study aims to investigate the involvement of TIMP-3 in the chemoresistance of laryngeal carcinoma. We showed that TIMP-3 expression was significantly decreased in chemoresistant laryngeal carcinoma tissues compared with chemosensitivity tissues. Patients with low TIMP-3 expression exhibited poorer overall survival than those with high TIMP-3 expression. Moreover, cisplatin-resistant Hep-2 cells (Hep-2/R) were associated with the inhibition of mitochondrial membrane potential (MtMP) depolarization after cisplatin challenge. In addition, cisplatin resulted in a more pronounced mitochondrial cytochrome c release into the cytoplasm in Hep-2 cells than in their resistant variants. Overexpression of TIMP-3 by an adenovirus encoding TIMP-3 cDNA remarkably enhanced cisplatin-induced apoptosis, cytochrome c release, and caspase activation in Hep-2/R cells, thereby sensitizing cancer cells to cisplatin. On the other hand, downregulation of TIMP-3 markedly inhibited cisplatin-induced apoptosis in Hep-2 cells through attenuating mitochondria-dependent pathway activation. Taken together, these results demonstrate that decreased TIMP-3 expression may contribute to cisplatin resistance via inhibition of mitochondria-dependent apoptosis, indicating that forced TIMP-3 expression may be a useful strategy to improve the efficacy of cisplatin to treat laryngeal carcinoma.

Chen J, Zhou C, Li J, et al.
miR‑21‑5p confers doxorubicin resistance in gastric cancer cells by targeting PTEN and TIMP3.
Int J Mol Med. 2018; 41(4):1855-1866 [PubMed] Free Access to Full Article Related Publications
Drug resistance and disease recurrence are major obstacles to the effective treatment of cancer, including gastric cancer (GC). However, the mechanisms of drug resistance remain to be fully elucidated. The present study investigated the roles of microRNA (miR)‑21‑5p in the doxorubicin (DOX) resistance of GC cells and the underlying mechanisms. miR‑21‑5p expression levels were identified to be inversely correlated with two well‑known tumor suppressor genes, phosphatase and tensin homologue and tissue inhibitor of matrix metalloproteinases 3, and were upregulated in GC cell lines in proportion to their degree of resistance. Suppressing miR‑21‑5p expression partially sensitized SGC7901/DOX cells to DOX, suggesting that knockdown of miR‑21‑5p expression may be used as a therapeutic strategy to improve GC cell resistance. Importantly, increased miR‑21‑5p expression levels at diagnosis were correlated with clinicopathological characteristics including advanced stage and poor prognosis, further implying that a relapse of GC may be a consequence of miR‑21‑5p upregulation, thus providing evidence for the potential utility of miR‑21‑5p antagonism to sensitize GC cells to DOX chemotherapy.

Laco J, Kovarikova H, Chmelarova M, et al.
Analysis of DNA methylation and microRNA expression in NUT (nuclear protein in testis) midline carcinoma of the sinonasal tract: a clinicopathological, immunohistochemical and molecular genetic study.
Neoplasma. 2018; 65(1):113-123 [PubMed] Related Publications
The aim of this study was a detailed clinicopathological investigation of sinonasal NUT midline carcinoma (NMC), including analysis of DNA methylation and microRNA (miRNA) expression. Three (5%) cases of NMC were detected among 56 sinonasal carcinomas using immunohistochemical screening and confirmed by fluorescence in situ hybridization. The series comprised 2 males and 1 female, aged 46, 60, and 65 years. Two tumors arose in the nasal cavity and one in the maxillary sinus. The neoplasms were staged pT1, pT3, and pT4a (all cN0M0). All patients were treated by radical resection with adjuvant radiotherapy. Two patients died 3 and 8 months after operation, but one patient (pT1 stage; R0 resection) experienced no evidence of disease at 108 months. Microscopically, all tumors consisted of infiltrating nests of polygonal cells with vesicular nuclei, prominent nucleoli and basophilic cytoplasm. Abrupt keratinization was present in only one case. Immunohistochemically, there was a diffuse expression of cytokeratin (CK) cocktail, CK7, p40, p63, and SMARCB1/INI1. All NMCs tested negative for EBV and HPV infection. Two NMCs showed methylation of RASSF1 gene. All other genes (APC, ATM, BRCA1, BRCA2, CADM1, CASP8, CD44, CDH13, CDKN1B, CDKN2A, CDKN2B, CHFR, DAPK1, ESR1, FHIT, GSTP1, HIC1, KLLN, MLH1a, MLH1b, RARB, TIMP3, and VHL) were unmethylated. All NMCs showed upregulation of miR-9 and downregulation of miR-99a and miR-145 and two cases featured also upregulation of miR-21, miR-143, and miR-484. In summary, we described three cases of sinonasal NMCs with novel findings on DNA methylation and miRNA expression, which might be important for new therapeutic strategies in the future.

Zhang Z, Wang J, Wang X, et al.
MicroRNA-21 promotes proliferation, migration, and invasion of cervical cancer through targeting TIMP3.
Arch Gynecol Obstet. 2018; 297(2):433-442 [PubMed] Related Publications
BACKGROUND: The expression of microRNA-21 (miR-21) is up-regulated in various cancers, including cervical cancer. However, the function of miR-21 through tissue inhibitor of metalloproteinase 3 (TIMP3) on the proliferation, migration, and invasion in cervical cancer is still unclear.
METHODS: A total of 60 paired fresh cervical cancer tissues, the corresponding adjacent non-neoplastic tissues and serum samples were collected from cervical cancer patients, while 60 matched normal tissues and serum samples were collected from the control group. MiR-21 expression was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). TIMP3 expression was evaluated by Western blot and qRT-PCR. Cell proliferation was determined by MTT assay. Migratory and invasive activities were assessed by cell migration and invasion assays, respectively. Luciferase reporter assay was employed to validate the direct targeting of TIMP3 by miR-21.
RESULTS: MiR-21 was up-regulated in cervical cancer tissues and serum samples, in contrast, TIMP3 was down-regulated in cervical cancer tissues. MiR-21 promoted the proliferation, viability and the migratory and invasive activities of cervical cancer cells through targeting TIMP3. Overexpression of TIMP3 attenuated the positive effects of miR-21.
CONCLUSIONS: These findings provide a novel insight into the molecular functions of miR-21 in cervical cancer, which may be used as a diagnostic and prognostic biomarker for the treatment of cervical cancer in the future.

Chen J, Gu Y, Shen W
MicroRNA-21 functions as an oncogene and promotes cell proliferation and invasion via TIMP3 in renal cancer.
Eur Rev Med Pharmacol Sci. 2017; 21(20):4566-4576 [PubMed] Related Publications
OBJECTIVE: Renal cell carcinoma (RCC) displays an increasing incidence and mortality rate worldwide in recent years. More and more evidence identified microRNAs function as positive or negative regulatory factors in many cancers, but the role of miR-21 in RCC remains unclear.
PATIENTS AND METHODS: Relative expression levels of miR-21 in human RCC tissue samples and RCC-derived cell lines were measured using quantitative real-time Polymerase Chain Reaction (PCR). Clinical features were collected to further study the relationship between the miR-21 level and clinicopathologic variables. Loss- and gain- of miR-21 experiments were employed to measure the influence of miR-21 in cell proliferation, apoptosis, invasion and migration. Downstream target gene was confirmed by using luciferase and Western blotting assays.
RESULTS: MiR-21 significantly over-expressed in RCC tissues and cell lines than normal groups. Higher miR-21 expression level indicated larger tumor sizes, more lymph metastasis and advanced tumor node metastasis (TNM) stage. Knocking down miR-21 inhibited the cell growth, invasion and migration abilities but promoted the cell apoptosis, while over-expressing miR-21 promoted cell growth and metastasis. Furthermore, TIMP3 was confirmed as a direct target of moR-21 and inhibition of TIMP3 reserved the effect of down-regulating miR-21 in RCC cells.
CONCLUSIONS: Our study demonstrated miR-21 was significantly over-expressed and functioned as a tumor oncogene via TIMP3 in RCC, which could provide a potential target for RCC diagnosis and therapy.

Dong X, Hou Q, Chen Y, Wang X
Diagnostic Value of the Methylation of Multiple Gene Promoters in Serum in Hepatitis B Virus-Related Hepatocellular Carcinoma.
Dis Markers. 2017; 2017:2929381 [PubMed] Free Access to Full Article Related Publications
This study sought to evaluate the diagnostic value of the methylation of multiple gene promoters in serum in hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC). A total of 343 participants were enrolled, including 98 patients with HCC, 75 patients with liver cirrhosis (LC), 90 patients with chronic hepatitis B (CHB), and 80 healthy individuals.

Du L, Ma S, Wen X, et al.
Oral squamous cell carcinoma cells are resistant to doxorubicin through upregulation of miR‑221.
Mol Med Rep. 2017; 16(3):2659-2667 [PubMed] Free Access to Full Article Related Publications
Oral squamous cell carcinoma (OSCC) cells are usually resistant to doxorubicin, resulting in limited application of doxorubicin in OSCC treatment. MicroRNA (miR)‑221 has been reported to be involved in the development of OSCC; however, it remains unclear if and how miR‑221 is implicated in modulating the sensitivity of OSCC cells to doxorubicin. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was used to assess miR‑221 expression in OSCC cells in response to doxorubicin treatment. In addition, the SCC4 and SCC9 OSCC cell lines were transfected with anti‑miR‑221 oligonucleotides and cell viability and apoptosis following doxorubicin treatment were evaluated using an MTT assay and Annexin V‑fluorescein isothiocyanate/Hoechst double staining, respectively. The mRNA and protein expression levels of tissue inhibitor of metalloproteinase‑3 (TIMP3) in anti‑miR‑221‑transfected cells were assessed using RT‑qPCR and western blot analysis, respectively. Furthermore, a luciferase reporter assay was performed to investigate whether TIMP3 may be a direct target gene of miR‑221. To explore the roles of TIMP3 in miR‑221‑mediated cell responses, TIMP3 expression was silenced following transfection with TIMP3‑targeting small interfering (si)RNA in cells overexpressing miR‑221, and cell viability and apoptosis in response to doxorubicin treatment were measured. The results of the present study demonstrated that miR‑221 expression was upregulated in SCC4 and SCC9 cells following treatment with doxorubicin. However, inhibiting the doxorubicin‑induced upregulation of miR‑221 through transfection with anti‑miR‑221 oligonucleotides led to an increase in the sensitivity of OSCC cells to doxorubicin. In addition, the results indicated that TIMP3 was a direct target of miR‑221 in OSCC cells, as determined by a 3'‑untranslated region luciferase reporter assay. Co‑transfection of cells with anti‑miR‑221 oligonucleotides and TIMP3‑specific small interfering RNA resulted in reduced sensitivity to doxorubicin compared with the cells transfected with the miR‑221 inhibitor alone. In conclusion, these results indicated that OSCC cells are resistant to doxorubicin through upregulation of miR‑221, which in turn downregulates TIMP3. Therefore, silencing miR‑221 or upregulating TIMP3 may be considered promising therapeutic approaches to enhance the sensitivity of OSCC to doxorubicin.

Tsai CH, Yang DY, Lin CY, et al.
Sphingosine-1-phosphate suppresses chondrosarcoma metastasis by upregulation of tissue inhibitor of metalloproteinase 3 through suppressing miR-101 expression.
Mol Oncol. 2017; 11(10):1380-1398 [PubMed] Free Access to Full Article Related Publications
Chondrosarcoma is the second most common primary malignancy form of bone cancer, exhibiting resistance to chemotherapy and radiation therapy as well as developing high metastasis ability in late-stage tumors. Thus, understanding the metastatic processes of chondrosarcoma is considered a strategy for the treatment of this disease. Sphingosine 1-phosphate (S1P), a bioactive sphingolipid, is produced intracellularly by sphingosine kinase (SphK) and is regarded as a second signaling molecule that regulates inflammation, proliferation, angiogenesis, and metastasis. However, the effect of S1P on chondrosarcoma remains uncertain. As demonstrated by the transwell, immunoblotting, and real-time PCR analyses, we found that S1P inhibited cell migration and MMP-2 expression through the upregulation of the tissue inhibitor of metalloproteinase-3 (TIMP-3) expression in human chondrosarcoma cells. Additionally, we also showed that microRNA (miRNA)-101, which targets the 3' untranslated region (3'UTR) of TIMP-3, decreased significantly following S1P treatment. After transfection with miR-101 mimics, the S1P-regulated cell migration and TIMP-3 expression were both reversed. Furthermore, we also showed that the S1P-inhibited cell migration is mediated through the c-Src/MEK/ERK signaling axis. Meanwhile, the in vivo study indicated that overexpression of SphK1 decreases chondrosarcoma metastasis to the lungs. Our results illustrate the clinical significance between SphK1, TIMP-3, and miR-101 in human chondrosarcoma patients. Taken together, our results suggest that S1P and miR-101 may prove to be potential therapeutic targets for future chondrosarcoma treatment.

Stephen JK, Chen KM, Merritt J, et al.
Methylation markers differentiate thyroid cancer from benign nodules.
J Endocrinol Invest. 2018; 41(2):163-170 [PubMed] Related Publications
PURPOSE: The incidence of thyroid cancer (TC) is increasing. Cytology by itself cannot distinguish TC from some benign nodules especially in certain subtypes of TC. Our immediate goal is to identify DNA methylation markers for early detection of TC and to molecularly differentiate TC subtypes from benign nodules.
METHODS: Promoter methylation status of 21 candidate genes was examined on formalin-fixed paraffin-embedded tissue (FFPE) utilizing quantitative methylation-specific polymerase chain reaction (QMSP) in a retrospective cohort of 329 patients (56% white, 29% African American, 61% female) comprising 71 normal thyroid, 83 benign nodules [follicular adenomas (FA)], 90 follicular TC (FTC) and 85 papillary TC (PTC). All genes were analyzed individually (Kruskal-Wallis and Wilcoxon rank sum tests) and in combination (logistic regression models) to identify genes whose methylation levels might best separate groups.
RESULTS: Combination gene panels TPO and UCHL1 (ROC = 0.607, sensitivity 78%) discriminated FTC from FA, and RASSF1 and TPO (ROC = 0.881, sensitivity 78%) discriminated FTC from normal. Methylation of TSHR distinguished PTC from FTC (ROC = 0.701, sensitivity 84%) and PTC from FA (ROC = 0.685, sensitivity 70%). The six gene panel of TIMP3, RARB2, SERPINB5, RASSF1, TPO and TSHR, which differentiates PTC from normal thyroid, had the best combination sensitivity (91%) and specificity (81%) of the panels addressing discrimination of cancer tissue.
CONCLUSIONS: Aberrant gene methylation used in combination panels may be useful clinically in differentiating FTC and PTC from benign nodules. If confirmed in additional studies, these findings could help reduce the over diagnosis of thyroid cancer and surgeries related to over diagnosis.

Galani V, Lampri E, Varouktsi A, et al.
Genetic and epigenetic alterations in meningiomas.
Clin Neurol Neurosurg. 2017; 158:119-125 [PubMed] Related Publications
Meningiomas originate from the arachnoid layer of the meninges and divided histologically into three grades: benign (grade I), atypical (grade II), and malignant meningiomas (grade III). Genetic alterations in grade I meningiomas include frequent deletions of chromosomal locus 22q12 and NF2 gene mutations and uncommon somatic SMARCB1 and SMARCE1gene mutations; In grade II meningiomas, chromosomal losses occur on 1p, 22q, 14q, 18q, 10, and 6q, and gains on 20q, 12q, 15q, 1q, 9q, and 17q; In grade III meningiomas, losses have been recognized on 6q, 10, and 14q and alterations of PTEN, CDKN2A and CDKN2B genes. Epigenetic alterations in meningiomas include hypermethylation of the tumor suppressor genes p73 in grade I meningiomas and TIMP3 GSTP1, MEG3, HOXA6, HOXA9, PENK, WNK2 and UPK3A genes with an increasing frequency according to grade. Abnormal expression of IGF signaling family genes and Wnt signaling pathway is associated with meningioma progression. MiRNA expression profiling of meningiomas show downregulation of miR-29c-3p, miR-200a, miR-145 and miR- 219-5p and upregulation of miR-21 miR-335 and miR-190a levels. In conclusion, extensive genetic and epigenetic alterations exist in meningiomas that may help assessing prognosis. In addition, since miRNA expression may be modified by artificial miRNAs, new effective therapeutic strategies may be developed especially for resistant or high grade meningiomas.

Haimes JD, Stewart CJR, Kudlow BA, et al.
Uterine Inflammatory Myofibroblastic Tumors Frequently Harbor ALK Fusions With IGFBP5 and THBS1.
Am J Surg Pathol. 2017; 41(6):773-780 [PubMed] Related Publications
Inflammatory myofibroblastic tumor (IMT) can occur in a number of anatomic sites, including the uterus. Like its soft tissue counterpart, uterine IMT frequently expresses ALK and harbors ALK genetic rearrangements. The aim of this study is to fully characterize the genetic fusions that occur in uterine IMT. We studied 11 uterine IMTs with typical histology and 8 uterine myxoid smooth muscle tumors (5 leiomyomas, 1 smooth muscle tumor of uncertain malignant potential, and 2 leiomyosarcomas) in which the differential of IMT was considered, using a RNA-sequencing-based fusion assay to detect genetic fusions involving ALK, ROS1, RET, NTRK1/3, and other genes. ALK was expressed in 10 of 11 IMTs and 1 tumor initially categorized as a myxoid leiomyoma (granular cytoplasmic staining with paranuclear accentuation). Fusion transcripts involving ALK were identified in 9 of 10 ALK immunopositive IMTs, with 3 harboring IGFBP5-ALK, 3 harboring THBS1-ALK, 2 harboring FN1-ALK, and 1 harboring TIMP3-ALK. Among the smooth muscle tumors, IGFBP5-ALK fusion transcript was identified in only 1 ALK immunopositive case. Further review revealed that although a diagnosis of IMT was considered for the ALK immunopositive myxoid leiomyoma, this diagnosis was not initially rendered only because fluorescence in situ hybridization analysis was interpreted as negative for ALK genetic rearrangement; this case is best reclassified as an IMT. Notably, all the ALK fusions identified in our study included the transmembrane domain-encoding exon 19 of ALK. Our findings confirm the high frequency of ALK fusions in uterine IMT, with an enrichment of novel 5' ALK fusion partners (IGFBP5, THBS1, and TIMP3) and exon 19-containing ALK fusion. Given that IGFBP5 and FN1 are both situated on the same chromosome as ALK, fluorescence in situ hybridization analysis for ALK rearrangement may not be reliable and a negative result should not exclude a diagnosis of uterine IMT if the histologic features and ALK immunostaining findings are supportive.

Strzelczyk JK, Gołąbek K, Cuber P, et al.
Comparison of Selected Protein Levels in Tumour and Surgical Margin in a Group of Patients with Oral Cavity Cancer.
Biochem Genet. 2017; 55(4):322-334 [PubMed] Related Publications
Oral cavity cancer belongs to head-and-neck squamous cell carcinoma group. The purpose of the study was to assess the levels of certain proteins in a tumour and surgical margin in a group of patients with oral cavity cancer. The levels of DAPK1, MGMT, CDH1, SFRP1, SFRP2, RORA, TIMP3, p16, APC and RASSF1 proteins were measured by ELISA in tissue homogenates. The protein levels of DAPK1, MGMT, CDH1, SFRP2 and RASSF1 were significantly higher in tumour tissue than in the margin, contrary to TIMP3 which was lower in the tumour itself. DAPK1 level in the tumour was significantly higher in females than in males, the MGMT and p16 levels were lower in the tumours with lymph node metastasis (N1 + N2) than in N0 samples. The CDH1 expression was higher in a group with smoking habits, whereas TIMP3 was lower in this group. Changes in the levels of proteins in tumour and surgical margin may be either reflective of tumour occurrence and development, or they might be also responsible for the progress and reoccurrence of the disease. Levels of the studied proteins might be good prognostic factors; however, further studies are required.

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