Gene Summary

Gene:PLAT; plasminogen activator, tissue type
Aliases: TPA, T-PA
Summary:This gene encodes tissue-type plasminogen activator, a secreted serine protease that converts the proenzyme plasminogen to plasmin, a fibrinolytic enzyme. The encoded preproprotein is proteolytically processed by plasmin or trypsin to generate heavy and light chains. These chains associate via disulfide linkages to form the heterodimeric enzyme. This enzyme plays a role in cell migration and tissue remodeling. Increased enzymatic activity causes hyperfibrinolysis, which manifests as excessive bleeding, while decreased activity leads to hypofibrinolysis, which can result in thrombosis or embolism. Alternative splicing of this gene results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tissue-type plasminogen activator
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (25)
Pathways:What pathways are this gene/protein implicaed in?
Show (4)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 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.

  • Tumor Suppressor Proteins
  • Polymerase Chain Reaction
  • Breast Cancer
  • Chromosome Deletion
  • Chromosome 8
  • Gene Expression Profiling
  • Mutation
  • Gene Amplification
  • Cohort Studies
  • Gene Deletion
  • Cancer DNA
  • Retinoic Acid
  • Pancreatic Cancer
  • Base Sequence
  • Tissue Plasminogen Activator
  • Prostate Cancer
  • Childhood Cancer
  • Transcriptome
  • MicroRNAs
  • Cancer Gene Expression Regulation
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
  • Transcriptional Regulator ERG
  • Lung Cancer
  • Infant
  • Bladder Cancer
  • Neoplasm Invasiveness
  • Newborns
  • Biomarkers, Tumor
  • France
  • Restriction Mapping
  • Translocation
  • Transforming Growth Factor beta
  • Cell Movement
  • Gene Regulatory Networks
  • Adolescents
  • Sequence Analysis, RNA
  • p53 Protein
  • Oligonucleotide Array Sequence Analysis
  • Karyotyping
  • Withanolides
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: PLAT (cancer-related)

Hung CY, Lee CH, Chiou HL, et al.
Praeruptorin-B Inhibits 12-O-Tetradecanoylphorbol-13-Acetate-Induced Cell Invasion by Targeting AKT/NF-κB via Matrix Metalloproteinase-2/-9 Expression in Human Cervical Cancer Cells.
Cell Physiol Biochem. 2019; 52(6):1255-1266 [PubMed] Related Publications
BACKGROUND/AIMS: Praeruptorins, a seselin-type coumarin, possess anti-inflammatory and antitumor promoting properties. However, molecular mechanisms through which Praeruptorin-B (Pra-B) exerts an antimetastatic effect on cervical cancer cells remain unclear.
METHODS: Cell viability was examined using the MTT assay, whereas cell migration and invasion were examined using the Boyden chamber assay. Western blotting and RT-PCR were performed to investigate the inhibitory effect of Pra-B on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-2/-9 (MMP-2/-9) expression in HeLa cells. The findings of the luciferase assay confirmed the inhibitory effect of Pra-B on TPA-induced transcriptional activity of MMP2/-9 in HeLa cells.
RESULTS: Pra-B inhibited TPA-induced metastatic ability of human cervical cancer cells without any significant toxicity. Pra-B suppressed TPA-induced mRNA and protein expression and transcriptional activity of MMP-2/-9 in HeLa cells. Furthermore, Pra-B inhibited AKT phosphorylation but did not affect the MAPK pathway. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 (a PI3K inhibitor) reduced cell invasion and MMP-2/-9 expression and transcriptional activity. In addition, Pra-B attenuated TPA-induced nuclear translocation of NF-κB-p65/-p50, which reduced Ikk-α phosphorylation in HeLa cells. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 reduced NF-κB nuclear translocation.
CONCLUSION: These results suggested that Pra-B-mediated inhibition of TPA-induced cell metastasis involved the suppression of p-AKT/NF-κB via MMP-2/-9 expression in HeLa cells. Pra-B can be a potential antimetastatic agent against cervical cancer.

Genov N, Basti A, Abreu M, Relógio A
Temporal Splicing Switches in Elements of the TNF-Pathway Identified by Computational Analysis of Transcriptome Data for Human Cell Lines.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Alternative splicing plays an important role in numerous cellular processes and aberrant splice decisions are associated with cancer. Although some studies point to a regulation of alternative splicing and its effector mechanisms in a time-dependent manner, the extent and consequences of such a regulation remains poorly understood. In the present work, we investigated the time-dependent production of isoforms in two Hodgkin lymphoma cell lines of different progression stages (HD-MY-Z, stage IIIb and L-1236, stage IV) compared to a B lymphoblastoid cell line (LCL-HO) with a focus on tumour necrosis factor (TNF) pathway-related elements. For this, we used newly generated time-course RNA-sequencing data from the mentioned cell lines and applied a computational pipeline to identify genes with isoform-switching behaviour in time. We analysed the temporal profiles of the identified events and evaluated in detail the potential functional implications of alterations in isoform expression for the selected top-switching genes. Our data indicate that elements within the TNF pathway undergo a time-dependent variation in isoform production with a putative impact on cell migration, proliferation and apoptosis. These include the genes

Xia J, Ozaki I, Matsuhashi S, et al.
Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Hypoxia-inducible factor 1 (HIF-1) plays important roles in cancer cell biology. HIF-1α is reportedly activated by several factors, including protein kinase C (PKC), in addition to hypoxia. We investigated the role of PKC isoforms and the effects of vitamin K2 (VK2) in the activation process of HIF-1α. Human hepatocellular carcinoma (HCC)-derived Huh7 cells were cultured under normoxic and hypoxic (1% O₂) conditions with or without the PKC stimulator TPA. The expression, transcriptional activity and nuclear translocation of HIF-1α were examined under treatment with PKC inhibitors, siRNAs against each PKC isoform and VK2. Hypoxia increased the expression and activity of HIF-1α. TPA increased the HIF-1α activity several times under both normoxic and hypoxic conditions. PKC-δ siRNA-mediated knockdown, PKC-δ inhibitor (rottlerin) and pan-PKC inhibitor (Ro-31-8425) suppressed the expression and transcriptional activity of HIF-1α. VK2 significantly inhibited the TPA-induced HIF-1α transcriptional activity and suppressed the expression and nuclear translocation of HIF-1α induced by TPA without altering the HIF-1α mRNA levels. These data indicate that PKC-δ enhances the HIF-1α transcriptional activity by increasing the nuclear translocation, and that VK2 might suppress the HIF-1α activation through the inhibition of PKC in HCC cells.

Zhong C, Mai Y, Gao H, et al.
Mitochondrial targeting of TR3 is involved in TPA induced apoptosis in breast cancer cells.
Gene. 2019; 693:61-68 [PubMed] Related Publications
TPA is considered to be a tumor promoting molecule that induces the expression of COX-2 protein. However, it is contradictory to find that TPA can induce tumor cell apoptosis and exert antitumor activity. Therefore, the role of TPA in tumorigenesis and development has not yet been elucidated. Here we show that TPA can promote the apoptosis of breast cancer cells and increase the ratio of Bax/Bcl-2. It is suggested that TPA may induce apoptosis of breast cancer cells through mitochondrial apoptosis pathway. Further studies showed that TPA could cause mitochondrial dysfunction and trigger mitochondrial apoptotic pathway. In mechanism, the mitochondrial targeting of TR3 is involved in TPA induced apoptosis in breast cancer cells. In conclusion, our findings suggest that TPA can play a role in inhibiting cancer by inducing apoptosis and TR3 is expected to be a new target for cancer treatment.

Liang Y, Zhang C, Ma MH, Dai DQ
Identification and prediction of novel non-coding and coding RNA-associated competing endogenous RNA networks in colorectal cancer.
World J Gastroenterol. 2018; 24(46):5259-5270 [PubMed] Free Access to Full Article Related Publications
AIM: To identify and predict the competing endogenous RNA (ceRNA) networks in colorectal cancer (CRC) by bioinformatics analysis.
METHODS: In the present study, we obtained CRC tissue and normal tissue gene expression profiles from The Cancer Genome Atlas project. Differentially expressed (DE) genes (DEGs) were identified. Then, upregulated and downregulated miRNA-centered ceRNA networks were constructed by analyzing the DEGs using multiple bioinformatics approaches. DEmRNAs in the ceRNA networks were identified in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using KEGG Orthology Based Annotation System 3.0. The interactions between proteins were analyzed using the STRING database. Kaplan-Meier survival analysis was conducted for DEGs and real time quantitative polymerase chain reaction (RT-qPCR) was also performed to validate the prognosis-associated lncRNAs in CRC cell lines.
RESULTS: Eighty-one DElncRNAs, 20 DEmiRNAs, and 54 DEmRNAs were identified to construct the ceRNA networks of CRC. The KEGG pathway analysis indicated that nine out of top ten pathways were related with cancer and the most significant pathway was "colorectal cancer". Kaplan-Meier survival analysis showed that the overall survival was positively associated with five DEGs (IGF2-AS, POU6F2-AS2, hsa-miR-32, hsa-miR-141, and SERPINE1) and it was negatively related to three DEGs (LINC00488, hsa-miR-375, and PHLPP2). Based on the STRING protein database, it was found that SERPINE1 and PHLPP2 interact with AKT1. Besides, SERPINE1 can interact with VEGFA, VTN, TGFB1, PLAU, PLAUR, PLG, and PLAT. PHLPP2 can interact with AKT2 and AKT3. RT-qPCR revealed that the expression of IGF2-AS, POU6F2-AS2, and LINC00488 in CRC cell lines was consistent with the
CONCLUSION: CeRNA networks play an important role in CRC. Multiple DEGs are related with clinical prognosis, suggesting that they may be potential targets in tumor diagnosis and treatment.

Lee YS, Lee CH, Bae JT, et al.
Inhibition of skin carcinogenesis by suppression of NF-κB dependent ITGAV and TIMP-1 expression in IL-32γ overexpressed condition.
J Exp Clin Cancer Res. 2018; 37(1):293 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Interleukin-32 (IL-32) has been associated with various diseases. Previous studies have shown that IL-32 inhibited the development of several tumors. However, the role of IL-32γ, an isotype of IL-32, in skin carcinogenesis remains unknown.
METHODS: We compared 7,12-Dimethylbenz[a]anthracene/12-O-Tetradecanoylphorbol-13-acetate (DMBA/TPA)-induced skin carcinogenesis in wild type (WT) and IL-32γ-overexpressing mice to evaluate the role of IL-32γ. We also analyzed cancer stemness and NF-κB signaling in skin cancer cell lines with or without IL-32γ expression by western blotting, quantitative real-time PCR and immunohistochemistry analysis.
RESULTS: Carcinogen-induced tumor incidence in IL-32γ mice was significantly reduced in comparison to that in WT mice. Infiltration of inflammatory cells and the expression levels of pro-inflammatory mediators were decreased in the skin tumor tissues of IL-32γ mice compared with WT mice. Using a genome-wide association study analysis, we found that IL-32 was associated with integrin αV (ITGAV) and tissue inhibitor of metalloproteinase-1 (TIMP-1), which are critical factor for skin carcinogenesis. Reduced expression of ITGAV and TIMP-1 were identified in DMBA/TPA-induced skin tissues of IL-32γ mice compared to that in WT mice. NF-κB activity was also reduced in DMBA/TPA-induced skin tissues of IL-32γ mice. IL-32γ decreased cancer cell sphere formation and expression of stem cell markers, and increased chemotherapy-induced cancer cell death. IL-32γ also downregulated expression of ITGAV and TIMP-1, accompanied with the inhibition of NF-κB activity. In addition, IL-32γ expression with NF-κB inhibitor treatment further reduced skin inflammation, epidermal hyperplasia, and cancer cell sphere formation and downregulated expression levels of ITGAV and TIMP-1.
CONCLUSIONS: These findings indicated that IL-32γ suppressed skin carcinogenesis through the inhibition of both stemness and the inflammatory tumor microenvironment by the downregulation of TIMP-1 and ITGAV via inactivation of NF-κB signaling.

Jin H, Kim HS, Seo GS, Lee SH
A new chalcone derivative, 3-phenyl-1-(2,4,6-tris(methoxymethoxy)phenyl)prop-2-yn-1-one), inhibits phorbol ester-induced metastatic activity of colorectal cancer cells through upregulation of heme oxygenase-1.
Eur J Pharmacol. 2018; 841:1-9 [PubMed] Related Publications
Chalcone (1,3-diphenyl-2-propen-1-one) derivatives exert anti-cancer activity by targeting key molecules that can lead to carcinogenesis. We synthesized the chalcone derivative 3-phenyl-1-(2,4,6-tris(methoxymethoxy)phenyl)prop-2-yn-1-one (KB-34) and previously reported its anti-inflammatory activity in macrophages. In this study, we examined the anti-metastatic activity of KB-34 against human colorectal cancer (CRC) cells and elucidated its underlying molecular mechanisms. KB-34 treatment significantly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced migration, as well as the invasion and proliferation of CRC cells (HT-29 and SW620). TPA-induced activation of NF-κB was also markedly suppressed by KB-34 in HT-29 cells. KB-34 suppressed the expression of matrix metalloproteinase-7 (MMP-7) at both the mRNA and protein levels in TPA-stimulated CRC cells (HT-29 and SW620). We also demonstrated that induced heme oxygenase-1 (HO-1) expression in CRC cells (HT-29 and SW620) and HO-1 is required for KB-34-mediated suppression of the expression of MMP-7 in TPA-stimulated HT-29 cells. Additionally, the cyclin-dependent kinase inhibitor p21 was significantly induced by treatment with KB-34 in CRC cells (HT-29 and SW620). Knockdown of HO-1 prevented the induction of p21 expression by KB-34 in HT-29 cells. Furthermore, we also demonstrated that 5-fluorouracil (5-FU) together with KB-34 produced a significantly greater inhibition of growth and stimulation of apoptosis of HT-29 cells than did 5-FU alone. In conclusion, KB-34 inhibits the TPA-stimulated metastatic potential of HT-29 cells by induction of HO-1 and may be a promising anti-cancer agent in chemotherapeutic strategies for CRC.

Davaadelger B, Murphy AR, Clare SE, et al.
Mechanism of Telapristone Acetate (CDB4124) on Progesterone Receptor Action in Breast Cancer Cells.
Endocrinology. 2018; 159(10):3581-3595 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Progesterone is a steroid hormone that plays an important role in the breast. Progesterone exerts its action through binding to progesterone receptor (PR), a transcription factor. Deregulation of the progesterone signaling pathway is implicated in the formation, development, and progression of breast cancer. Next-generation selective progesterone receptor modulators (SPRMs) have potent antiprogestin activity and are selective for PR, reducing the off-target effects on other nuclear receptors. To date, there is limited information on how the newer generation of SPRMs, specifically telapristone acetate (TPA), affect PR function at the molecular level. In this study, T47D breast cancer cells were used to investigate the molecular mechanism by which TPA antagonizes PR action. Global profiling of the PR cistrome and interactome was done with chromatin immunoprecipitation sequencing (ChIP-seq) and rapid immunoprecipitation mass spectrometry. Validation studies were done on key genes and interactions. Our results demonstrate that treatment with the progestin (R5020) alone resulted in robust PR recruitment to the chromatin, and addition of TPA reduced PR recruitment globally. TPA significantly changed coregulator recruitment to PR compared with R5020. Upon conservative analysis, three proteins (TRPS1, LASP1, and AP1G1) were identified in the R5020+TPA-treated group. Silencing TRPS1 with small interfering RNA increased PR occupancy to the known PR regulatory regions and attenuated the inhibition of gene expression after TPA treatment. TRPS1 silencing alleviated the inhibition of proliferation by TPA. In conclusion, TPA decreases PR occupancy on chromatin and recruits coregulators such as TRPS1 to the PR complex, thereby regulating PR target gene expression and associated cellular responses.

Lu Y, Li C, Chen H, Zhong W
Identification of hub genes and analysis of prognostic values in pancreatic ductal adenocarcinoma by integrated bioinformatics methods.
Mol Biol Rep. 2018; 45(6):1799-1807 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the world, and more molecular mechanisms should be illuminated to meet the urgent need of developing novel detection and therapeutic strategies. We analyzed the related microarray data to find the possible hub genes and analyzed their prognostic values using bioinformatics methods. The mRNA microarray datasets GSE62452, GSE15471, GSE102238, GSE16515, and GSE62165 were finally chosen and analyzed using GEO2R. The overlapping genes were found by Venn Diagrams, functional and pathway enrichment analyses were performed using the DAVID database, and the protein-protein interaction (PPI) network was constructed by STRING and Cytoscape. OncoLnc, which was linked to TCGA survival data, was used to investigate the prognostic values. In total, 179 differentially expressed genes (DEGs) were found in PDAC, among which, 130 were up-regulated genes and 49 were down-regulated. DAVID showed that the up-regulated genes were significantly enriched in extracellular matrix and structure organization, collagen catabolic and metabolic process, while the down-regulated genes were mainly involved in proteolysis, reactive oxygen species metabolic process, homeostatic process and cellular response to starvation. From the PPI network, the 21 nodes with the highest degree were screened as hub genes. Based on Molecular Complex Detection (MCODE) plug-in, the top module was formed by ALB, TGM, PLAT, PLAU, EGF, MMP7, MMP1, LAMC2, LAMA3, LAMB3, COLA1, FAP, CDH11, COL3A1, ITGA2, and VCAN. OncoLnc survival analysis showed that, high expression of ITGA2, MMP7, ITGB4, ITGA3, VCAN and PLAU may predict poor survival results in PDAC. The present study identified hub genes and pathways in PDAC, which may be potential targets for its diagnosis, treatment, and prognostic prediction.

Kim SJ, Pham TH, Bak Y, et al.
7-Methoxy-luteolin-8-C-β-6-deoxy-xylo-pyranos-3-uloside exactly (mLU8C-PU) isolated from Arthraxon hispidus inhibits migratory and invasive responses mediated via downregulation of MMP-9 and IL-8 expression in MCF-7 breast cancer cells.
Environ Toxicol. 2018; 33(11):1143-1152 [PubMed] Related Publications
7-Methoxy-luteolin-8-C-β-6-deoxy-xylo-pyranos-3-uloside (mLU8C-PU) is a glycosylflavone of luteolin isolated from Arthraxon hispidus (Thunb.). Luteolin is known to exert anti-migratory and anti-invasive effects on tumor cells. However, there are no reports on the effects of mLU8C-PU on tumor invasiveness and associated signaling pathways. In this study, we demonstrated the anti-migratory and anti-invasive effects of mLU8C-PU in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 breast cancer cells. We also investigated the effect of mLU8C-PU on invasion- related signal transducers, including protein kinase Cα (PKCα), c-Jun N terminal kinase (JNK), activator protein-1 (AP-1), and nuclear factor-kappa B (NF-ĸB). TPA-induced membrane translocation of PKCα, phosphorylation of JNK, and the nuclear translocations of AP-1 and NF-κB were downregulated by mLU8C-PU in MCF-7 cells. In addition, mLU8C-PU also inhibited matrix metalloproteinase-9 (MMP-9) and interleukin-8 (IL-8) expression. These results indicate that mLU8C-PU inhibits migratory and invasive responses in MCF-7 breast cancer cells by suppressing MMP-9 and IL-8 expression through mitigating TPA-induced PKCα, JNK activation, and the nuclear translocation of AP-1 and NF-κB. These results suggest that mLU8C-PU may be used as an anti-metastatic agent.

Sharma MC
Annexin A2 (ANX A2): An emerging biomarker and potential therapeutic target for aggressive cancers.
Int J Cancer. 2019; 144(9):2074-2081 [PubMed] Related Publications
ANX A2 is an important member of annexin family of proteins expressed on surface of endothelial cells (ECs), macrophages, mononuclear cells and various types of cancer cells. It exhibits high affinity binding for calcium (Ca

Su Z, Song J, Wang Z, et al.
Tumor promoter TPA activates Wnt/β-catenin signaling in a casein kinase 1-dependent manner.
Proc Natl Acad Sci U S A. 2018; 115(32):E7522-E7531 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The tumor promoter 12-

Banskota S, Dahal S, Kwon E, et al.
β-Catenin gene promoter hypermethylation by reactive oxygen species correlates with the migratory and invasive potentials of colon cancer cells.
Cell Oncol (Dordr). 2018; 41(5):569-580 [PubMed] Related Publications
PURPOSE: Over half of the colon cancer patients suffer from cancer-related events, mainly metastasis. Loss of β-catenin activity has previously been found to facilitate cancer cell dissociation and migration. Here, we aimed to investigate whether epigenetic silencing of β-catenin induces human colon cancer cell migration and/or invasion.
METHODS: HCT-116, Caco-2, HT-29 and SW620 cell migration and invasion capacities were assessed using scratch wound healing and Matrigel invasion assays, respectively. Confocal microscopy, qRT-PCR and Western blotting were performed to determine gene expression levels, whereas methylation-specific quantitative real-time PCR was used to assess the extent of β-catenin gene (CTNNB1) promoter methylation after treatment of the cells with TPA, hydrogen peroxide, 5-aza-2'-deoxycytidine and/or VAS2870.
RESULTS: We found that treatment of HT-29 and Caco-2 cells (differentiated and low metastatic) with 12-O-tetradecanoyl phorbol-13-acetate (TPA; a tumor promoter) suppressed E-cadherin and β-catenin expression at both the mRNA and protein levels and, in addition, enhanced cell migration. Furthermore, we found that the CTNNB1 gene promoter methylation levels were higher in the more invasive HCT-116 and SW620 colon cancer cells than in HT-29 and CCD-841 (normal colon epithelial) cells. We also found that TPA or hydrogen peroxide induced CTNNB1 gene promoter methylation to a higher extent in HT-29 and CCD-841 cells than in HCT-116 and SW620 cells, and that the degree of CTNNB1 gene promoter methylation positively correlated with cell dissociation and migration. In addition, we found that co-treatment with 5-aza-2'-deoxycytidine (decitabine, a DNA methyl transferase inhibitor) and VAS2870 (a NADPH oxidase inhibitor) almost completely blocked the invasion of TPA-treated HT-29 and TPA-untreated HCT-116 and SW620 cells, and that these inhibitions surpassed those of the cells treated with decitabine or VAS2870 alone.
CONCLUSIONS: From our data we conclude that the extent of CTNNB1 gene promoter methylation by reactive oxygen species correlates with the migratory and invasive abilities of colon cancer cells. Our results suggest that epigenetic regulation of CTNNB1 may serve as a novel avenue to block colon cancer cell migration and invasion.

Wu X, Tommasi di Vignano A, Zhou Q, et al.
The ARE-binding protein Tristetraprolin (TTP) is a novel target and mediator of calcineurin tumor suppressing function in the skin.
PLoS Genet. 2018; 14(5):e1007366 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
An increased incidence of skin inflammatory diseases is frequently observed in organtransplanted patients being treated with calcineurin inhibitor-based immunosuppressive agents. The mechanism of increased skin inflammation in this context has however not yet been clarified. Here we report an increased inflammation following inhibition of calcineurin signaling seen in both chemically induced mouse skin tumors and in tumors grafted from H-rasV12 expressing primary human keratinocytes (HKCs). Following UVB or TPA treatment, we specifically found that deletion of the calcineurin gene in mouse keratinocytes (MKCs) resulted in increased inflammation, and this was accompanied by the enhanced production of pro-inflammatory cytokines, such as TNFα, IL-8 and CXCL1. Furthermore, expression of the RNA-binding protein, tristetraprolin (TTP) was down-regulated in response to calcineurin inhibition, wherein TTP was shown to negatively regulate the production of pro-inflammatory cytokines in keratinocytes. The induction of TTP following TPA or UVB treatment was attenuated by calcineurin inhibition in keratinocytes, and correspondingly, disruption of calcineurin signaling down-regulated the amounts of TTP in both clinical and H-rasV12-transformed keratinocyte tumor models. Our results further demonstrated that calcineurin positively controls the stabilization of TTP in keratinocytes through a proteasome-dependent mechanism. Reducing the expression of TTP functionally promoted tumor growth of H-rasV12 expressing HKCs, while stabilizing TTP expression counteracted the tumor-promoting effects of calcineurin inhibition. Collectively these results suggest that calcineurin signaling, acting through TTP protein level stabilization, suppresses keratinocyte tumors by downregulating skin inflammation.

Chun SY, Kim S, Nam KS, Lee KS
Anti-metastatic potential of a proton beam is regulated by p38 MAPK/c-Fos signaling pathway in TPA-treated HepG2 human hepatocellular carcinoma.
Biomed Pharmacother. 2018; 99:904-912 [PubMed] Related Publications
A proton beam therapy is considered the next generation radio-therapeutic tool for liver cancer treatments. However, its effect on metastasis has not been fully elucidated. Herein, we assessed the effects of a proton beam on the metastatic potential in HepG2, Hep3B and SK-Hep1 hepatocellular carcinomas. The result showed that a proton beam suppressed TPA-induced cell migration and invasion in HepG2 cells, but not in Hep3B and SK-Hep1 cells. In addition, matrix metalloproteinase-9 (MMP-9) activity and mRNA expressions were reversed by proton beam irradiation in TPA-treated HepG2 cells only. Furthermore, a proton beam suppressed TPA-induced gene expressions of urokinase plasminogen activator (uPA), uPA receptor (uPAR), Snail-1 and vascular endothelial growth factor (VEGF) in HepG2 cells in a dose-dependent manner. Moreover, we found that proton beam irradiation restrained p38 MAPK phosphorylation and c-Fos expression. Therefore, the result demonstrates that the anti-metastatic effects of a proton beam in TPA-treated HepG2 cells are associated with the inhibition of MMP-9 activity and the down-regulations of MMP-9, uPA, uPAR, Snail-1 and VEGF gene expression via the p38 MAPK/c-Fos signaling pathway. Taken together, this investigation suggests that the establishment of a customized proton beam therapeutic strategy for each liver cancer type is necessary to improve therapeutic efficiency.

Kong YH, Xu SP
Salidroside prevents skin carcinogenesis induced by DMBA/TPA in a mouse model through suppression of inflammation and promotion of apoptosis.
Oncol Rep. 2018; 39(6):2513-2526 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Salidroside (SR) is a main component of Rhodiola rosea L. and exhibits a variety of pharmacologic properties. The present study was carried out to explore the potential effect of SR against skin cancer induced by 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13‑acetate (TPA) in female Institute for Cancer Research (ICR) mice and to reveal the underlying molecular targets regulated by SR. The mice were randomly divided into 4 groups: control, DMBA/TPA, DMBA/TPA+SR (20 mg/kg) and DMBA/TPA+SR (40 mg/kg). SR was administered to mice five times a week after DMBA treatments. In our study, we found that SR dose-dependently ameliorated skin cancer incidence and the multiplicity in the animal models by reducing the release of inflammation-related cytokines, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-18 (IL-18), interleukin-6 (IL-6), cyclooxygenase 2 (COX2) and transforming growth factor β-1 (TGF-β1). Suppression of the nuclear factor (NF)-κB signaling pathway by SR was effective to prevent skin carcinogenesis. Furthermore, TUNEL analysis indicated that compared to the DMBA/TPA group, enhanced apoptosis was observed in the DMBA/TPA+SR group. In addition, p53 expression levels were increased by SR in the DMBA/TPA-induced mice. Therefore, SR was effective for inducing apoptosis during skin cancer progression triggered by DMBA/TPA. Consistently, p21, p53 upregulated modulator of apoptosis (PUMA), Bax and caspase-3 were highly induced by SR to enhance the apoptotic response for preventing skin cancer. Moreover, in vitro, we found that SR dramatically reduced the inflammatory response, while enhancing the aoptotic response by blocking NF-κB and activating caspase-3 pathways, respectively. In addition, flow cytometric analysis further confirmed the induction of apoptosis by SR in DMBA-treated cells in vitro. Taken together, the in vivo and in vitro studies illustrated that SR might be a promising compound to reduce skin cancer risk.

Yang Y, Yang I, Cao M, et al.
Fucoxanthin Elicits Epigenetic Modifications, Nrf2 Activation and Blocking Transformation in Mouse Skin JB6 P+ Cells.
AAPS J. 2018; 20(2):32 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Nuclear factor erythroid-2-related factor-2 (Nrf2 or NFE2L2) is a master regulator of the anti-oxidative stress response, which is involved in the defense against many oxidative stress/inflammation-mediated diseases, including anticancer effects elicited by an increasing number of natural products. Our previous studies showed that the epigenetic modification of the Nrf2 gene plays a key role in restoring the expression of Nrf2. In this study, we aimed to investigate the epigenetic regulation of Nrf2 by astaxanthin (AST) and fucoxanthin (FX), carotenoids which are abundant in microalgae and seaweeds, in mouse skin epidermal JB6 P+ cells. FX induced the anti-oxidant response element (ARE)-luciferase and upregulated the mRNA and protein levels of Nrf2 and Nrf2 downstream genes in HepG2-C8 cells overexpressing the ARE-luciferase reporter. Both FX and AST decreased colony formation in 12-Otetradecanoylphorbol-13-acetate (TPA)-induced transformation of JB6 P+ cells. FX decreased the methylation of the Nrf2 promoter region in the JB6 P+ cells by the bisulfite conversion and pyrosequencing. Both FX and AST significantly reduced DNA methyltransferase (DNMT) activity but did not affect histone deacetylase (HDAC) activity in JB6 P+ cells. In summary, our results show that FX activates the Nrf2 signaling pathway, induces the epigenetic demethylation of CpG sites in Nrf2 and blocks the TPA-induced transformation of JB6 P+ cells, indicating the potential health-promoting effects of FX in skin cancer prevention.

Hernández-Franco P, Silva M, Franco R, et al.
Lead facilitates foci formation in a Balb/c-3T3 two-step cell transformation model: role of Ape1 function.
Environ Sci Pollut Res Int. 2018; 25(12):12150-12158 [PubMed] Related Publications
Several possible mechanisms have been examined to gain an understanding on the carcinogenic properties of lead, which include among others, mitogenesis, alteration of gene expression, oxidative damage, and inhibition of DNA repair. The aim of the present study was to explore if low concentrations of lead, relevant for human exposure, interfere with Ape1 function, a base excision repair enzyme, and its role in cell transformation in Balb/c-3T3. Lead acetate 5 and 30 μM induced APE1 mRNA and upregulation of protein expression. This increase in mRNA expression is consistent throughout the chronic exposure. Additionally, we also found an impaired function of Ape1 through molecular beacon-based assay. To evaluate the impact of lead on foci formation, a Balb/c-3T3 two-step transformation model was used. Balb/c-3T3 cells were pretreated 1 week with low concentrations of lead before induction of transformation with n-methyl-n-nitrosoguanidine (MNNG) (0.5 μg/mL) and 12-O-tetradecanoylphorbol-13-acetate (TPA) (0.1 μg/mL) (a classical two-step protocol). Morphological cell transformation increased in response to lead pretreatment that was paralleled with an increase in Ape1 mRNA and protein overexpression and an impairment of Ape1 activity and correlating with foci number. In addition, we found that lead pretreatment and MNNG (transformation initiator) increased DNA damage, determined by comet assay. Our data suggest that low lead concentrations (5, 30 μM) could play a facilitating role in cellular transformation, probably through the impaired function of housekeeping genes such as Ape1, leading to DNA damage accumulation and chromosomal instability, one of the most important hallmarks of cancer induced by chronic exposures.

Patrício MI, Barnard AR, Green AL, et al.
A clinical-grade gene therapy vector for pharmacoresistant epilepsy successfully overexpresses NPY in a human neuronal cell line.
Seizure. 2018; 55:25-29 [PubMed] Related Publications
PURPOSE: Epilepsy is a common neurological condition characterised by recurrent unprovoked seizures and often treatable with appropriate medication. However, almost 30% of cases are pharmacoresistant and while a proportion of these may be amenable to resective surgery, a gene therapy approach could be an attractive alternative option. Neuropeptide Y (NPY) has anticonvulsant and anti-epileptogenic properties in animal models of temporal lobe epilepsy when delivered by an adeno-associated viral (AAV) vector. Here we sought to demonstrate successful secretion of NPY from AAV-transduced human neuronal cells, which would be essential in planning any clinical trial.
METHODS: A human neuroblastoma cell line (SH-SY5Y) was used to assess in vitro whether an AAV vector manufactured to clinical-grade protocols would be effective at transducing these cells to express NPY. Optimal transduction efficiency was first achieved with retinoic acid and tetradecanoylphorpol-13-acetate (TPA) treatment, prior to expose to AAV1-green fluorescent protein (GFP) reporter vector, AAV1-NPY therapeutic vector or sham treated with no vector. Levels of NPY in cell supernatants were determined using two antibody-based methods RESULTS: We found that the levels of NPY released into the cell culture media supernatant, and protein extracts of the cell pellet, were significantly higher following exposure to AAV1-NPY than when compared to either a control GFP reporter vector (AAV1-GFP) or sham treated controls.
CONCLUSION: This first demonstration that an AAV-NPY construct can successfully transduce human neuronal cells supports the pre-clinical development of a clinical trial using AAV-based NPY for pharmacoresistant epilepsy.

Minotti L, Baldassari F, Galasso M, et al.
A long non-coding RNA inside the type 2 transglutaminase gene tightly correlates with the expression of its transcriptional variants.
Amino Acids. 2018; 50(3-4):421-438 [PubMed] Related Publications
The long non-coding RNAs (lncRNAs) are matter of intense investigation as potential regulators of gene expression. In the case of the transglutaminase 2 gene (TGM2) the databases of genome sequence indicate location of a lncRNA (LOC107987281) within the first intron. This lncRNA is 1000 bp long, arises from 2 exons and starts few nucleotides 3' of the first splicing site of translated TGM2. We have analysed correlations between expression of LOC107987281 lncRNA and TGM2 mRNA by real-time PCR in K562 cell line untreated or treated with the anticancer drugs TPA (12-O-tetradecanoylphorbol-13-acetate), Docetaxel and Doxorubicin. In the treated cells the lncRNA increase follows the trend of TGM2 transcript. To validate this finding we used HumanExon1_0ST Affymetrix; chip data were background-adjusted, quantile-normalized and summarized using robust multi-array average analysis implemented in the R package. The probesets recognize sequences inside each exon, near intronic splicing sites and others located in the untranslated regions of TGM2 gene. The analysis of total RNA samples in GEO datasets from K562, HL-60, THP-1 and U937 cell lines, untreated or treated with TPA in replicated experiments confirmed our earlier results. These demonstrate correlation between LOC107987281 and TGM2 mRNA in the cell lines (K562, HL60 and THP-1) where increased levels of TGM2 mRNA are produced. Additional array study on 358 samples of several normal and paired tumor tissues leads to the same conclusions, indicating a correlation between full-length TGM2 mRNA and LOC107987281 lncRNA in relation to the development of several tumors.

Fukushima K, Takahashi K, Kurokawa A, et al.
Involvement of LPA receptor-5 in the enhancement of cell motile activity by phorbol ester and anticancer drug treatments in melanoma A375 cells.
Biochem Biophys Res Commun. 2018; 496(1):225-230 [PubMed] Related Publications
Lysophosphatidic acid (LPA) signaling through six subtypes of LPA receptors (LPA

Wu WS, You RI, Cheng CC, et al.
Snail collaborates with EGR-1 and SP-1 to directly activate transcription of MMP 9 and ZEB1.
Sci Rep. 2017; 7(1):17753 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The Snail transcription factor plays as a master regulator of epithelial mesenchymal transition (EMT), one of the steps of tumor metastasis. Snail enhances expressions of a lot of mesenchymal genes including the matrix degradation enzyme matrix metalloproteinases 9 (MMP9) and the EMT transcription factor zinc finger E-box binding homeobox 1 (ZEB1), however, the underlying mechanisms are not clarified. Herein, we investigated how Snail upregulated transcription of ZEB1 and MMP9 induced by the tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate (TPA) in hepatoma cell HepG2. According to deletion mapping and site directed mutagenesis analysis, the TPA-responsive elements on both MMP9 and ZEB1 promoters locate on a putative EGR1 and SP1 overlapping region coupled with an upstream proposed Snail binding motif TCACA. Consistently, chromatin immunoprecipitation (ChIP) assay showed TPA triggered binding of Snail, EGR1 and SP1 on MMP9 and ZEB1 promoters. Double ChIP further indicated TPA induced association of Snail with EGR1 and SP1 on both promoters. Also, electrophoresis mobility shift assay revealed TPA enhanced binding of Snail with a MMP9 promoter fragment. According to shRNA techniques, Snail was essential for gene expression of both ZEB1 and MMP9. In conclusion, Snail transactivates genes involved in tumor progression via direct binding to a specific promoter region.

Pisano G, Roy A, Ahmed Ansari M, et al.
Interferon-γ-inducible protein 16 (IFI16) is required for the maintenance of Epstein-Barr virus latency.
Virol J. 2017; 14(1):221 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Epstein-Barr virus (EBV) exhibits both lytic and latent (Lat. I, II, and III) phases in an infected individual. It's during the latent phase of EBV that all EBV-associated cancers, including Burkitt's lymphoma, nasopharyngeal carcinoma and lymphoproliferative disease arise. Interferon-γ-inducible protein 16 (IFI16) is a well-established innate immune sensor and viral transcriptional regulator involved in response to invading DNA viruses. During latency, IFI16 remains in the nucleus, in part bound to the EBV genome; however, neither its role in EBV lytic cycle or latency has been established.
METHODS: Short interfering RNA against IFI16 and IFI16 overexpression were used to identify the role of IFI16 in the maintenance of EBV latency I. We also studied how induction of the lytic cycle affected IFI16 using the EBV positive, latently infected Akata or MUTU-1 cell lines. Akata cells were induced with TPA and MUTU-1 cells with TGF-β up to 96 h and changes in IFI16 protein were analyzed by Western blotting and immunofluorescence microscopy. To assess the mechanism of IFI16 decrease, EBV DNA replication and late lytic transcripts were blocked using the viral DNA polymerase inhibitor phosphonoacetic acid.
RESULTS: Knockdown of IFI16 mRNA by siRNA resulted in enhanced levels of EBV lytic gene expression from all temporal gene classes, as well as an increase in the total EBV genome abundance, whereas overexpression of exogenous IFI16 reversed these effects. Furthermore, 96 h after induction of the lytic cycle with either TPA (Akata) or TGF-β (MUTU-1), IFI16 protein levels decreased up to 80% as compared to the EBV-negative cell line BJAB. Reduction in IFI16 was observed in cells expressing EBV lytic envelope glycoprotein. The decreased levels of IFI16 protein do not appear to be dependent on late lytic transcripts of EBV but suggest involvement of the immediate early, early, or a combination of both gene classes.
CONCLUSIONS: Reduction of IFI16 protein levels following lytic cycle induction, as well as reactivation from latency after IFI16 mRNA knockdown suggests that IFI16 is crucial for the maintenance of EBV latency. More importantly, these results identify IFI16 as a unique host factor protein involved in the EBV lifecycle, making it a potential therapeutic target to combat EBV-related malignancies.

Lin CY, Cho CF, Bai ST, et al.
ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT.
Sci Rep. 2017; 7(1):15108 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Lung cancer has a very high prevalence of brain metastasis, which results in a poor clinical outcome. Up-regulation of a disintegrin and metalloproteinase 9 (ADAM9) in lung cancer cells is correlated with metastasis to the brain. However, the molecular mechanism underlying this correlation remains to be elucidated. Since angiogenesis is an essential step for brain metastasis, microarray experiments were used to explore ADAM9-regulated genes that function in vascular remodeling. The results showed that the expression levels of vascular endothelial growth factor A (VEGFA), angiopoietin-2 (ANGPT2), and tissue plasminogen activator (PLAT) were suppressed in ADAM9-silenced cells, which in turn leads to decreases in angiogenesis, vascular remodeling, and tumor growth in vivo. Furthermore, simultaneous high expression of ADAM9 and VEGFA or of ADAM9 and ANGPT2 was correlated with poor prognosis in a clinical dataset. These findings suggest that ADAM9 promotes tumorigenesis through vascular remodeling, particularly by increasing the function of VEGFA, ANGPT2, and PLAT.

Meng L, Wang M, Du Z, et al.
Cell Signaling Pathway in 12-O-Tetradecanoylphorbol-13-acetate-Induced LCN2 Gene Transcription in Esophageal Squamous Cell Carcinoma.
Biomed Res Int. 2017; 2017:9592501 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
LCN2 is involved in various cellular functions, including transport of small hydrophobic molecules, protection of MMP9 from proteolytic degradation, and regulating innate immunity. LCN2 is elevated in multiple human cancers, frequently being associated with tumor size, stage, and invasiveness. Our previous studies have shown that LCN2 expression could be induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in esophageal squamous cell carcinoma (ESCC) by the binding of five nucleoproteins (MISP, KLF10, KLF15, PPP1R18, and RXR

Wang L, Zhang R, You X, et al.
The steady-state level of CDK4 protein is regulated by antagonistic actions between PAQR4 and SKP2 and involved in tumorigenesis.
J Mol Cell Biol. 2017; 9(5):409-421 [PubMed] Related Publications
CDK4 is crucial for G1-to-S transition of cell cycle. It is well established that ubiquitin-mediated degradations of CDK inhibitors and cyclins are pivotal for the timely and unidirectional progression of cell cycle. However, how CDK4 itself is modulated by ubiquitin-mediated degradation has been elusive. Here we report that the steady-state level of CDK4 is controlled by PAQR4, a member of the progestin and adipoQ receptor family, and SKP2, an E3 ubiquitin ligase. Knockdown of PAQR4 leads to reduction of cell proliferation, accompanied by reduced protein level of CDK4. PAQR4 reduces polyubiquitination and degradation of CDK4. PAQR4 interacts with the C-terminal lobe of CDK4. On the other hand, SKP2 also interacts with the C-terminal lobe of CDK4 and enhances polyubiquitination and degradation of CDK4. Importantly, PAQR4 and SKP2 bind to the same region in CDK4, and PAQR4 competes with SKP2 for the binding, thereby abrogating SKP2-mediated ubiquitination of CDK4. Using a two-stage DMBA/TPA-induced skin cancer model, we find that PAQR4-deleted mice are resistant to chemical carcinogen-induced tumor formation. Collectively, our findings reveal that the steady-state level of CDK4 is controlled by the antagonistic actions between PAQR4 and SKP2, contributing to modulation of cell proliferation and tumorigenesis.

Okumura K, Kagawa N, Saito M, et al.
CENP-R acts bilaterally as a tumor suppressor and as an oncogene in the two-stage skin carcinogenesis model.
Cancer Sci. 2017; 108(11):2142-2148 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
CENP-R is a component of the CENP-O complex, including CENP-O, CENP-P, CENP-Q, CENP-R, and CENP-U and is constitutively localized to kinetochores throughout the cell cycle in vertebrates. CENP-R-deficient chicken DT40 cells are viable and show a very minor effect on mitosis. To investigate the functional roles of CENP-R in vivo, we generated CENP-R-deficient mice (Cenp-r

Mohanan S, Horibata S, Anguish LJ, et al.
PAD2 overexpression in transgenic mice augments malignancy and tumor-associated inflammation in chemically initiated skin tumors.
Cell Tissue Res. 2017; 370(2):275-283 [PubMed] Related Publications
We previously found that transgenic mice overexpressing MMTV-FLAG-hPAD2 (PAD2OE) developed spontaneous skin lesions, with a subset of these lesions progressing to invasive squamous cell carcinoma (SCC). The goal of this report was to better understand the potential mechanisms by which PAD2 overexpression promotes skin cancer. Here, PAD2OE mice were treated with the carcinogen, 9,10-dimethyl-1,2-benzanthracene and with O-tetradecanoylphorbol-13-acetate and then scored for papilloma formation. Additionally, tumor sections were evaluated for evidence of tumor cell invasion and inflammation. We found that the total number of papillomas was significantly increased in PAD2OE mice compared to controls. Histopathologic analysis of the lesions found that in PAD2OE skin tumors progressed to invasive SCC more frequently than controls. Additionally, we found that PAD2OE lesions were highly inflamed, with a dense inflammatory cell infiltrate and an associated increase in nuclear phospho-STAT3 (signal transducer and activator of transcription 3) in the transgenic tumors. These data suggest that overexpression of the hPAD2 transgene in the epidermis increases the malignant conversion rate of benign tumors by promoting an inflammatory microenvironment.

You D, Jung SP, Jeong Y, et al.
Wild-type p53 controls the level of fibronectin expression in breast cancer cells.
Oncol Rep. 2017; 38(4):2551-2557 [PubMed] Related Publications
Aberrant fibronectin (FN) expression is associated with poor prognosis, cell adhesion, and cell motility in a variety of cancer cells. In this study, we investigated the relationship between p53 and FN expression in breast cancer cells. Basal FN expression was significantly decreased by treatment with the p53 activator III, RITA, in MCF7 breast cancer cells with wild-type p53. In addition, overexpression of wild-type p53 markedly decreased the level of FN expression in p53-mutant breast cancer cells. To examine the mechanism underlying the relationship between p53 and FN expression, we treated MCF7 breast cancer cells with the tumor promoter TPA (12-O-tetradecanoylphorbol-13-acetate). Our results showed that basal FN expression was increased by TPA treatment in a time-dependent manner. In contrast, the level of p53 expression was decreased by TPA treatment. However, the expression of FN and p53 was not altered by TPA in p53-mutant breast cancer cells. Furthermore, the alterations in FN and p53 expression in response to TPA were prevented by a specific MEK inhibitor, UO126. Finally, we demonstrated that TPA triggers degradation of p53 through the proteasomal pathway in MCF7 cells. TPA-induced FN expression was decreased by the proteasome inhibitor MG132. Under the same condition, p53 protein expression, but not mRNA expression, was reversed by MG132. Taken together, our data demonstrate that the level of FN expression is associated with the status and expression of p53 in breast cancer cells.

Marchesi I, Sanna L, Fais M, et al.
12-O-tetradecanoylphorbol-13-acetate and EZH2 inhibition: A novel approach for promoting myogenic differentiation in embryonal rhabdomyosarcoma cells.
J Cell Physiol. 2018; 233(3):2360-2365 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is a soft tissue sarcoma that arises from muscle precursors affecting predominately children and young adults. It can be divided into two main classes: embryonal (eRMS) and alveolar rhabodomyosarcomas (aRMS). Despite the expression of early muscle specific genes, RMS cells fail to complete myogenesis even in differentiation conditions. We previously demonstrated that Enhancer Zeste of Homolog 2 (EZH2), the catalytic subunits of PRC2 complex, contributes to inhibit muscle differentiation in eRMS and its down-regulation causes a partial recovery of myogenesis. 12-O-tetradecanoylphorbol-13-acetate (TPA) is a molecule able to induce differentiation in eRMS with a mechanism that involves the protein kinase C (PKC). In this paper we report that treatment with TPA reduces the expression of EZH2 without affecting levels of H3K27me3. The combination of TPA with GSK126, an inhibitor of the catalytic activity of EZH2, has a synergic effect on the induction of muscle differentiation in RD rhabdomyosarcoma cells, suggesting a new therapeutic combinatory approach for RMS treatment.

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