Gene Summary

Gene:ETS1; ETS proto-oncogene 1, transcription factor
Aliases: p54, ETS-1, EWSR2, c-ets-1
Summary:This gene encodes a member of the ETS family of transcription factors, which are defined by the presence of a conserved ETS DNA-binding domain that recognizes the core consensus DNA sequence GGAA/T in target genes. These proteins function either as transcriptional activators or repressors of numerous genes, and are involved in stem cell development, cell senescence and death, and tumorigenesis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Jul 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein C-ets-1
Source:NCBIAccessed: 31 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 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.

  • Zinc Fingers
  • Oligonucleotide Array Sequence Analysis
  • Messenger RNA
  • Cancer Gene Expression Regulation
  • Lung Cancer
  • Young Adult
  • TRPC Cation Channels
  • Immunohistochemistry
  • Proto-Oncogene Proteins
  • Molecular Sequence Data
  • MAP Kinase Signaling System
  • Breast Cancer
  • Cell Movement
  • Down-Regulation
  • Biomarkers, Tumor
  • Protein Binding
  • Proto-Oncogene Protein c-ets-1
  • Cervical Cancer
  • Chromosome 11
  • Adenocarcinoma
  • Gene Expression Profiling
  • Tumor Suppressor Proteins
  • Vimentin
  • MicroRNAs
  • TGFA
  • Disease Progression
  • Transcriptional Activation
  • Neoplasm Metastasis
  • Proto-Oncogene Proteins c-ets
  • Cell Proliferation
  • Promoter Regions
  • Mutation
  • Neoplasm Invasiveness
  • DNA-Binding Proteins
  • RNA Interference
  • Cancer DNA
  • Gene Expression
  • Base Sequence
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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: ETS1 (cancer-related)

Nazir SU, Kumar R, Singh A, et al.
Breast cancer invasion and progression by MMP-9 through Ets-1 transcription factor.
Gene. 2019; 711:143952 [PubMed] Related Publications
Ets-1 is one of the crucial member of transcription factor family which share a unique DNA binding domain. It is predominantly expressed in various tumor subtypes and has shown its association in the regulation of various important genes which include ECM-degrading proteases. Our study aimed to understand the mechanism(s) in the pathogenesis of breast carcinogenesis by Ets-1 transcription factor and its downstream target gene MMP-9. Role of Ets-1 in MCF-7 and MDA-MB-231 breast cancer cells was studied by RNA-interference in combination with pull down and ChIP assays to identify the regulation of MMP-9 in these cell lines. Our results showed that transfection of Ets-1 siRNA in breast cancer cell lines resulted in downregulation of Ets-1 and MMP-9. Ets-1 knock down also showed reduced cell invasion and altered expression of EMT markers. Moreover, we could also predict that MMP-9 gene promoter harbors a binding site for Ets-1 transcription factor may be responsible in direct transactivation of Ets-1 along with EMT markers. Phenotypic changes and molecular alterations that may result in increased aggressiveness/invasiveness and metastatic nature of cancerous cells may lead to changes in EMT markers. Therefore, these findings may suggest a plausible role of Ets-1 dependent regulation of MMP-9 gene and may have a significant impact on breast carcinogenesis.

Cao B, Tan S, Tang H, et al.
miR‑512‑5p suppresses proliferation, migration and invasion, and induces apoptosis in non‑small cell lung cancer cells by targeting ETS1.
Mol Med Rep. 2019; 19(5):3604-3614 [PubMed] Free Access to Full Article Related Publications
An increasing number of microRNA (miRNA) have been demonstrated to serve as molecular biomarkers for tumor cell progression. miR‑512‑5p was revealed as oncogenic regulator in several types of cancer. However, whether and how miR‑512‑5p regulates non‑small cell lung cancer (NSCLC) remains unclear. In the present study, the expression of miR‑512‑5p was detected in NSCLC tissues and cell lines. Then, the proliferation, migration, invasion and apoptosis in NSCLC A549 and H1299 cell lines were detected when miR‑512‑5p was overexpressed. Furthermore, the underlying mechanism was identified. The level of miR‑512‑5p was decreased in NSCLC tissues and in NSCLC cells compared with adjacent normal tissues and normal lung tissue cell lines. miR‑512‑5p mimics inhibited the cell proliferation, migration, invasion and induced apoptosis in A549 and H1299 cells. In addition, a luciferase reporter assay suggested that overexpression of miR‑512‑5p may decrease the expression of the E26 transformation specific‑1 (ETS1) gene; it was subsequently verified that downregulation of the ETS1 gene inhibited cell proliferation and migration and induced cell apoptosis in A549 and H1299 cells, and ETS1 small interfering RNA in the presence of an miR‑512‑5p inhibitor reversed the effect. The data described in the present study suggest that miR‑512‑5p may be a tumor suppressor and a potential treatment target in NSCLC.

Rahman MR, Islam T, Gov E, et al.
Identification of Prognostic Biomarker Signatures and Candidate Drugs in Colorectal Cancer: Insights from Systems Biology Analysis.
Medicina (Kaunas). 2019; 55(1) [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world, but early diagnosis ameliorates the survival of CRC. This report aimed to identify molecular biomarker signatures in CRC. We analyzed two microarray datasets (GSE35279 and GSE21815) from the Gene Expression Omnibus (GEO) to identify mutual differentially expressed genes (DEGs). We integrated DEGs with protein⁻protein interaction and transcriptional/post-transcriptional regulatory networks to identify reporter signaling and regulatory molecules; utilized functional overrepresentation and pathway enrichment analyses to elucidate their roles in biological processes and molecular pathways; performed survival analyses to evaluate their prognostic performance; and applied drug repositioning analyses through Connectivity Map (CMap) and geneXpharma tools to hypothesize possible drug candidates targeting reporter molecules. A total of 727 upregulated and 99 downregulated DEGs were detected. The PI3K/Akt signaling, Wnt signaling, extracellular matrix (ECM) interaction, and cell cycle were identified as significantly enriched pathways. Ten hub proteins (ADNP, CCND1, CD44, CDK4, CEBPB, CENPA, CENPH, CENPN, MYC, and RFC2), 10 transcription factors (ETS1, ESR1, GATA1, GATA2, GATA3, AR, YBX1, FOXP3, E2F4, and PRDM14) and two microRNAs (miRNAs) (miR-193b-3p and miR-615-3p) were detected as reporter molecules. The survival analyses through Kaplan⁻Meier curves indicated remarkable performance of reporter molecules in the estimation of survival probability in CRC patients. In addition, several drug candidates including anti-neoplastic and immunomodulating agents were repositioned. This study presents biomarker signatures at protein and RNA levels with prognostic capability in CRC. We think that the molecular signatures and candidate drugs presented in this study might be useful in future studies indenting the development of accurate diagnostic and/or prognostic biomarker screens and efficient therapeutic strategies in CRC.

Rodriguez-Aguayo C, Bayraktar E, Ivan C, et al.
PTGER3 induces ovary tumorigenesis and confers resistance to cisplatin therapy through up-regulation Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis.
EBioMedicine. 2019; 40:290-304 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Inflammatory mediator prostaglandin E2-prostaglandin E2 receptor EP3 (PTGER3) signaling is critical for tumor-associated angiogenesis, tumor growth, and chemoresistance. However, the mechanism underlying these effects in ovarian cancer is not known.
METHODS: An association between higher tumoral expression of PTGER3 and shorter patient survival in the ovarian cancer dataset of The Cancer Genome Atlas prompted investigation of the antitumor effects of PTGER3 downmodulation. PTGER3 mRNA and protein levels were higher in cisplatin-resistant ovarian cancer cells than in their cisplatin-sensitive counterparts.
FINDINGS: Silencing of PTGER3 via siRNA in cancer cells was associated with decreased cell growth and less invasiveness, as well as cell-cycle arrest and increased apoptosis, mediated through the Ras-MAPK/Erk-ETS1-ELK1/CFTR1 axis. Furthermore, sustained PTGER3 silencing with multistage vector and liposomal 2'-F-phosphorodithioate-siRNA-mediated silencing of PTGER3 combined with cisplatin resulted in robust antitumor effects in cisplatin-resistant ovarian cancer models.
INTERPRETATION: These findings identify PTGER3 as a potential therapeutic target in chemoresistant ovarian cancers expressing high levels of this oncogenic protein. FUND: National Institutes of Health/National Cancer Institute, USA.

Li S, Yan G, Yue M, et al.
MicroRNA‑766 inhibits the malignant biological behaviours of pancreatic ductal adenocarcinoma by directly targeting ETS1.
Mol Med Rep. 2019; 19(2):1380-1387 [PubMed] Related Publications
Increasing evidence indicates that numerous microRNAs (miRNAs) are altered in pancreatic ductal adenocarcinoma (PDAC), and their alterations significantly influence the malignant behaviour of PDAC. Therefore, identifying miRNAs associated with PDAC and their biological roles in the disease may provide promising therapeutic opportunities. Alteration of the expression of miRNA‑766 (miR‑766) has been previously reported in several types of human malignancy. However, to the best of our knowledge, whether miR‑766 exhibits different expression patterns in PDAC and its underlying functions in the progression of PDAC remain to be elucidated. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was used to detect miR‑766 expression levels in PDAC tissues and cell lines. The effects of miR‑766 upregulation on PDAC cell proliferation and invasion were evaluated using MTT and invasion assays, respectively. The mechanisms underlying the role of miR‑766 in PDAC cells were explored using bioinformatics analysis, luciferase reporter assay, RT‑qPCR and western blot analysis. It was found that miR‑766 was significantly downregulated in PDAC tissues and cell lines. The detailed roles of miR‑766 in the progression of PDAC were characterised using Panc‑1 and Aspc‑1 cell lines. The results revealed that the upregulation of miR‑766 restricted the proliferation and invasion of PDAC cells. Through a series of experiments, it was found that E26 transformation specific‑1 (ETS1) was a direct target of miR‑766 in PDAC cells. Furthermore, ETS1 knockdown simulated the inhibitory effects of the overexpression of miR‑766 on PDAC cells, whereas the effects of miR‑766 restoration on the PDAC cells were reversed by overexpressing ETS1. In conclusion, the findings of the present study demonstrate that miR‑766 offers potential as a therapeutic target for patients with PDAC.

Kleemann M, Schneider H, Unger K, et al.
Induction of apoptosis in ovarian cancer cells by miR-493-3p directly targeting AKT2, STK38L, HMGA2, ETS1 and E2F5.
Cell Mol Life Sci. 2019; 76(3):539-559 [PubMed] Related Publications
Apoptosis is a form of directed programmed cell death with a tightly regulated signalling cascade for the destruction of single cells. MicroRNAs (miRNAs) play an important role as fine tuners in the regulation of apoptotic processes. MiR-493-3p mimic transfection leads to the induction of apoptosis causing the breakdown of mitochondrial membrane potential and the activation of Caspases resulting in the fragmentation of DNA in several ovarian carcinoma cell lines. Ovarian cancer shows with its pronounced heterogeneity a very high death-to-incidence ratio. A target gene analysis for miR-493-3p was performed for the investigation of underlying molecular mechanisms involved in apoptosis signalling pathways. Elevated miR-493-3p levels downregulated the mRNA and protein expression levels of Serine/Threonine Kinase 38 Like (STK38L), High Mobility Group AT-Hook 2 (HMGA2) and AKT Serine/Threonine Kinase 2 (AKT2) by direct binding as demonstrated by luciferase reporter assays. Notably, the protein expression of RAF1 Proto-Oncogene, Serine/Threonine Kinase (RAF1) was almost completely downregulated by miR-493-3p. This interaction, however, was indirect and regulated by STK38L phosphorylation. In addition, RAF1 transcription was diminished as a result of reduced transcription of ETS proto-oncogene 1 (ETS1), another direct target of miR-493-3p. Taken together, our observations have uncovered the apoptosis inducing potential of miR-493-3p through its regulation of multiple target genes participating in the extrinsic and intrinsic apoptosis pathway.

Furlan A, Vercamer C, Heliot L, et al.
Ets-1 drives breast cancer cell angiogenic potential and interactions between breast cancer and endothelial cells.
Int J Oncol. 2019; 54(1):29-40 [PubMed] Free Access to Full Article Related Publications
Ets-1 transcription factor overexpression in breast cancers is associated with invasive features and is associated with a poor prognosis. Beyond its role in driving carcinoma cell invasion, in this study, we wished to determine whether Ets-1 overexpression in cancer cells promotes angiogenesis by creating a paracrine pro-invasive environment for endothelial cells as well. To address this question, we set up different co-culture models of cancer cells with endothelial cells. Conditioned media from cancer cells induced endothelial cell proliferation, migration and morphogenesis in matrix models. Of note, co-culture assays in three-dimensional matrix models also revealed the reciprocal induction of cancer cell morphogenesis by endothelial cells, in support of an angiocrine action on tumor cells. Ets-1 emerged as a key regulator of the angiogenic potential of breast cancer cells, favoring their ability to induce, in a paracrine manner, the morphogenesis of endothelial cells and also to physically interact with the latter. Nevertheless, Ets-1 overexpression in cancer cells also restrained their chemoattractive potential for endothelial cells both in Boyden chambers and in ex vivo 3D co-cultures. Finally, Ets-1 modulation in breast cancer cells qualitatively altered the angiogenic pattern of experimental in vivo tumors, with a balance between vessel recruitment and intratumoral small capillaries sprouting. Taken together, our data highlight a critical and intriguing role for Ets-1 in the angiogenic potential of breast cancer cells, and reveal another facet of Ets-1 oncogenic activities.

Li T, Chen Y, Zhang J, Liu S
LncRNA TUG1 promotes cells proliferation and inhibits cells apoptosis through regulating AURKA in epithelial ovarian cancer cells.
Medicine (Baltimore). 2018; 97(36):e12131 [PubMed] Free Access to Full Article Related Publications
This study aimed to assess the effect of long noncoding RNAs (lncRNAs) taurine-upregulated gene 1 (TUG1) on cells proliferation and apoptosis as well as its targeting genes in epithelial ovarian cancer (EOC) cells.Blank mimic, lncRNA TUG1 mimic, blank inhibitor, and lncRNA TUG1 inhibitor plasmids were transfected into SK-OV-3 (SKOV3) cells. Rescue experiment was performed by the transfection of lncRNA TUG1 inhibitor and Aurora kinase A (AURKA) mimic plasmids into SKOV3 cells. Cell counting kit-8 (CKK-8), annexin V-FITC (AV)-propidium iodide (PI) (AV-PI), quantitative polymerase chain reaction (qPCR), and western blot assays were performed to detect cells proliferation, apoptosis, RNA expression, and protein expression respectively.Cells proliferation was increased in lncRNA TUG1 mimic group and decreased in lncRNA TUG1 inhibitor group than normal control (NC) groups. Cells apoptosis rate was repressed after treatment with lncRNA TUG1 mimic and promoted after treatment with lncRNA TUG1 inhibitor. AURKA expression but not CLDN3, SERPINE1, or ETS1 expression was adversely regulated by lncRNA TUG1 mimic and inhibitor. After transferring lncRNA TUG1 (-) and AURKA (+) plasmids, cells proliferation was increased, while cells apoptosis rate was decreased in AURKA mimic (+)/lncRNA TUG1 inhibitor (-) group than NC (+)/lncRNA TUG1 (-) group, which suggested lncRNA TUG1 regulated cells proliferation and cells apoptosis through targeting AURKA.LncRNA TUG1 promotes cells proliferation and inhibits cells apoptosis through regulating AURKA in EOC cells.

Shao Z, Li Y, Dai W, et al.
ETS-1 induces Sorafenib-resistance in hepatocellular carcinoma cells via regulating transcription factor activity of PXR.
Pharmacol Res. 2018; 135:188-200 [PubMed] Related Publications
Transcription factor E26 transformation specific sequence 1 (ETS-1) is a primary regulator in the metastasis of human cancer cells, especially hepatocellular carcinoma (HCC) cells; and it would affect the prognosis of HCC patients who received chemotherapies. However, the regulatory role of ETS-1 in the resistance of HCC cells to molecular-targeting agent remains poorly understood. In the present work, we demonstrate that high ETS-1 expression correlates with poor prognosis of advanced HCC patients received Sorafenib treatment. Mechanistically, ETS-1 binds to nuclear Pregnane X receptor (PXR) directly and enhances PXR's transcription factor activity, which further leads to the induction of the PXR's downstream multi-drug resistance related genes. Overexpression of ETS-1 accelerates the metabolic clearance of Sorafenib in HCC cells and leads to the better survival and faster migration of those cells. The therapeutic studies show that ETS-1 promotes the Sorafenib-resistance of HCC tumor models and ETS-1 blockade enhances the anti-tumor capacity of Sorafenib by decreasing PXR activation. Thus, our study suggests that ETS-1 could enhance the activation of PXR and be a potential therapeutic target for overcoming Sorafenib resistance in HCC treatment.

Liao H, Pan Y, Pan Y, et al.
MicroRNA‑874 is downregulated in cervical cancer and inhibits cancer progression by directly targeting ETS1.
Oncol Rep. 2018; 40(4):2389-2398 [PubMed] Related Publications
An increasing number of studies have reported that microRNAs (miRNAs) are dysregulated in cervical cancer and serve critical roles in cervical oncogenesis and progression. Therefore, identifying the aberrantly expressed miRNAs implicated in the formation and progression of cervical cancer may provide key clues for the development of effective therapeutic targets in treating patients with this type of malignancy. In the present study, miRNA‑874 (miR‑874) was downregulated in cervical cancer tissues and cell lines, and this downregulation was associated with International Federation of Gynaecology and Obstetrics stage and lymph node metastasis. The restored expression of miR‑874 prohibited the proliferation, migration and invasion, but promoted the apoptosis of cervical cancer cells. In addition, E26 transformation specific‑1 (ETS1) was identified as the direct target of miR‑874 in cervical cancer. Inhibition of ETS1 served tumour‑suppressive roles similar to miR‑874 overexpression in cervical cancer cells. A series of rescue experiments revealed that restoring ETS1 expression abolished the tumour‑suppressing effects of miR‑874 in cervical cancer cells. Taken together, the results of the present study indicated that miR‑874 may serve as a tumour suppressor in cervical cancer by directly targeting ETS1. This function suggested that miR‑874 holds potential therapeutic applications in treating patients with this type of malignancy.

Huang J, Sun Y, Chen H, et al.
ADAMTS5 acts as a tumor suppressor by inhibiting migration, invasion and angiogenesis in human gastric cancer.
Gastric Cancer. 2019; 22(2):287-301 [PubMed] Related Publications
BACKGROUND: ADAMTS5 has been reported to be involved in the progression of several human tumors. Nevertheless, the role of ADAMTS5 in gastric cancer (GC) remains poorly defined.
METHODS: ADAMTS5 expression levels were analyzed by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) in GC cell lines and tissues, and the correlations between ADAMTS5 expression and clinicopathological features and survival were also examined. In vitro assays, including transwell assays, wound healing assays and cell adhesion assays, were employed to further explore the biological functions of ADAMTS5. A MAP kinase pathway microarray was used to identify the underlying mechanisms. The expression of ADAMTS5 and ETS1 and the microvessel density (MVD) were also analyzed using IHC to determine correlations with angiogenesis in GC.
RESULTS: ADAMTS5 expression was downregulated in gastric cancer tissues. Low expression of ADAMTS5 was associated with gender, histological type, degree of differentiation, M stage, TNM stage and vascular invasion, and was also an independent indicator of a poor prognosis for patients with GC. ADAMTS5 overexpression markedly inhibited GC cell migration and invasion and enhanced cell adhesion to the extracellular matrix (ECM), whereas knockdown of ADAMTS5 exerted the opposite effects. Furthermore, the ADAMTS5 expression status was negatively correlated with ETS1 expression and MVD.
CONCLUSION: ADAMTS5 is downregulated in GC and suppresses tumor metastasis and angiogenesis by inhibiting ETS1-mediated changes in MVD and potentially acts as a novel prognostic marker and a potential therapeutic target in human GC.

Zhai W, Ma J, Zhu R, et al.
MiR-532-5p suppresses renal cancer cell proliferation by disrupting the ETS1-mediated positive feedback loop with the KRAS-NAP1L1/P-ERK axis.
Br J Cancer. 2018; 119(5):591-604 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite the fact that miRNAs play pivotal roles in various human malignancies, their molecular mechanisms influencing RCC are poorly understood.
METHODS: The expression of miRNAs from RCC and paired normal renal specimens was analysed by a combined computational and experimental approach using two published datasets and qRT-PCR assays. The functional role of these miRNAs was further identified by overexpression and inhibition assays in vivo and in vitro. Western blots, luciferase assays, and chromatin immunoprecipitation were performed to investigate the potential mechanisms of these miRNAs.
RESULTS: Bioinformatics analysis and qRT-PCR revealed that miR-532-5p was one of the most heavily downregulated miRNAs. Overexpression of miR-532-5p inhibited RCC cell proliferation, while knockdown of miR-532-5p promoted cell proliferation. Mechanistic analyses indicated that miR-532-5p directly targets KRAS and NAP1L1. Interestingly, ETS1 suppressed the transcription of miR-532-5p by directly binding a special region of its promoter. Moreover, high levels of ETS1, as an oncogene in RCC, were significantly associated with poor survival in a large cohort of RCC specimens.
CONCLUSIONS: Our work presents a road map for the prediction and validation of a miR-532-5p/KRAS-NAP1L1/P-ERK/ETS1 axis feedback loop regulating cell proliferation, which could potentially provide better therapeutic avenues for treating RCC.

Kori M, Yalcin Arga K
Potential biomarkers and therapeutic targets in cervical cancer: Insights from the meta-analysis of transcriptomics data within network biomedicine perspective.
PLoS One. 2018; 13(7):e0200717 [PubMed] Free Access to Full Article Related Publications
The malignant neoplasm of the cervix, cervical cancer, has effects on the reproductive tract. Although infection with oncogenic human papillomavirus is essential for cervical cancer development, it alone is insufficient to explain the development of cervical cancer. Therefore, other risk factors such as host genetic factors should be identified, and their importance in cervical cancer induction should be determined. Although gene expression profiling studies in the last decade have made significant molecular findings about cervical cancer, adequate screening and effective treatment strategies have yet to be achieved. In the current study, meta-analysis was performed on cervical cancer-associated transcriptome data and reporter biomolecules were identified at RNA (mRNA, miRNA), protein (receptor, transcription factor, etc.), and metabolite levels by the integration of gene expression profiles with genome-scale biomolecular networks. This approach revealed already-known biomarkers, tumor suppressors and oncogenes in cervical cancer as well as various receptors (e.g. ephrin receptors EPHA4, EPHA5, and EPHB2; endothelin receptors EDNRA and EDNRB; nuclear receptors NCOA3, NR2C1, and NR2C2), miRNAs (e.g., miR-192-5p, miR-193b-3p, and miR-215-5p), transcription factors (particularly E2F4, ETS1, and CUTL1), other proteins (e.g., KAT2B, PARP1, CDK1, GSK3B, WNK1, and CRYAB), and metabolites (particularly, arachidonic acids) as novel biomarker candidates and potential therapeutic targets. The differential expression profiles of all reporter biomolecules were cross-validated in independent RNA-Seq and miRNA-Seq datasets, and the prognostic power of several reporter biomolecules, including KAT2B, PCNA, CD86, miR-192-5p and miR-215-5p was also demonstrated. In this study, we reported valuable data for further experimental and clinical efforts, because the proposed biomolecules have significant potential as systems biomarkers for screening or therapeutic purposes in cervical carcinoma.

Breunig C, Erdem N, Bott A, et al.
TGFβ1 regulates HGF-induced cell migration and hepatocyte growth factor receptor MET expression via C-ets-1 and miR-128-3p in basal-like breast cancer.
Mol Oncol. 2018; 12(9):1447-1463 [PubMed] Free Access to Full Article Related Publications
Breast cancer is the most common cancer in women worldwide. The tumor microenvironment contributes to tumor progression by inducing cell dissemination from the primary tumor and metastasis. TGFβ signaling is involved in breast cancer progression and is specifically elevated during metastatic transformation in aggressive breast cancer. In this study, we performed genomewide correlation analysis of TGFBR2 expression in a panel of 51 breast cancer cell lines and identified that MET is coregulated with TGFBR2. This correlation was confirmed at the protein level in breast cancer cell lines and human tumor tissues. Flow cytometric analysis of luminal and basal-like breast cancer cell lines and examination of 801 tumor specimens from a prospective cohort of breast cancer patients using reverse phase protein arrays revealed that expression of TGFBR2 and MET is increased in basal-like breast cancer cell lines, as well as in triple-negative breast cancer tumor tissues, compared to other subtypes. Using real-time cell analysis technology, we demonstrated that TGFβ1 triggered hepatocyte growth factor (HGF)-induced and MET-dependent migration in vitro. Bioinformatic analysis predicted that TGFβ1 induces expression of C-ets-1 as a candidate transcription factor regulating MET expression. Indeed, TGFβ1-induced expression of ETS1 and breast cancer cell migration was blocked by knockdown of ETS1. Further, we identified that MET is a direct target of miR-128-3p and that this miRNA is negatively regulated by TGFβ1. Overexpression of miR-128-3p reduced MET expression and abrogated HGF-induced cell migration of invasive breast cancer cells. In conclusion, we have identified that TGFβ1 regulates HGF-induced and MET-mediated cell migration, through positive regulation of C-ets-1 and negative regulation of miR-128-3p expression in basal-like breast cancer cell lines and in triple-negative breast cancer tissue.

Lee M, Kim KS, Fukushi A, et al.
Transcriptional Activation of Human GD3 Synthase (hST8Sia I) Gene in Curcumin-Induced Autophagy in A549 Human Lung Carcinoma Cells.
Int J Mol Sci. 2018; 19(7) [PubMed] Free Access to Full Article Related Publications
Curcumin, a natural polyphenolic compound isolated from the plant

Tajirika T, Tokumaru Y, Taniguchi K, et al.
DEAD-Box Protein RNA-Helicase DDX6 Regulates the Expression of HER2 and FGFR2 at the Post-Transcriptional Step in Gastric Cancer Cells.
Int J Mol Sci. 2018; 19(7) [PubMed] Free Access to Full Article Related Publications
The human DEAD/H-box RNA helicase DDX6 (RCK/p54) is a protein encoded by the fusion gene from the t(11;14)(q23;q32) chromosomal translocation observed in human B-cell lymphoma cell line RC-K8. DDX6 has a variety of functions such as translation initiation, pre-mRNA splicing, and ribosome assembly. However, details of the regulatory mechanism governing DDX6 and the functions of DDX6 are largely unknown. Previously, we reported that DDX6 is overexpressed in most malignant cell lines and clinical colorectal tumor samples and that DDX6 positively contributes to the pathogenesis of various cancers. In the current study, we aimed at revealing the function of DDX6 in HER2 and FGFR2 related human gastric cancer (GC) by using clinical samples and GC cell lines. DDX6 protein was overexpressed in about 60% of the clinical samples; HER2, in 35%; and FGFR2, in 30%, (

Millien G, Cao Y, O'Hara CJ, et al.
ETS1 regulates Twist1 transcription in a Kras
Clin Exp Metastasis. 2018; 35(3):149-165 [PubMed] Related Publications
Distinct members of the Ets family of transcription factors act as positive or negative regulators of genes involved in cellular proliferation, development, and tumorigenesis. In human lung cancer, increased ETS1 expression is associated with poor prognosis and metastasis. We tested whether ETS1 contributes to lung tumorigenesis by binding to Twist1, a gene involved in tumor cell motility and dissemination. We used a mouse lung cancer model with metastasis driven by conditionally activated Kras and concurrent tumor suppressor Lkb1 loss (Kras

Koessinger D, Albrecht V, Faber F, et al.
ETS-1 Expression Is Hypoxia-independent in Glioblastoma-derived Endothelial and Mesenchymal Stem-like Cells.
Anticancer Res. 2018; 38(6):3347-3355 [PubMed] Related Publications
BACKGROUND: Tumor cells infiltrating the brain are a typical hallmark of glioblastoma. Invasiveness of glioma cells has been associated with ETS proto-oncogene 1 (ETS-1). In non-glial tumors, ETS-1 expression has been linked to hypoxia. However, it is not known whether hypoxia regulates ETS-1 expression in glioblastoma.
MATERIALS AND METHODS: The spatial distribution of ETS-1 expression in primary glioblastoma was assessed using immunohistochemistry. ETS-1 expression in glioblastoma-derived mesenchymal stem-like cells (gbMSLCs) was determined using immunocytochemistry. The effect of hypoxia on ETS-1 expression of gbMSLCs, glioma cell lines and glioblastoma-derived endothelial cells was assessed using polymerase chain reaction and immunoblotting.
RESULTS: Our immunohistochemical studies revealed ETS-1 expression in stromal and endothelial glioblastoma cells. Stromal ETS-1 expression in glioblastoma correlated with microvessel density. gbMSLCs were found to express ETS-1. In all examined cell lines, ETS-1 transcription and expression were independent of hypoxia.
CONCLUSION: In glioblastoma, ETS-1-expression is not dependent on hypoxia, but correlates with tumor vascularization.

Chou NH, Lo YH, Wang KC, et al.
MiR-193a-5p and -3p Play a Distinct Role in Gastric Cancer: miR-193a-3p Suppresses Gastric Cancer Cell Growth by Targeting ETS1 and CCND1.
Anticancer Res. 2018; 38(6):3309-3318 [PubMed] Related Publications
BACKGROUND/AIM: MicroRNAs (miRNAs) are small non-protein-coding RNAs, that can be generated from the 5p or 3p arm of precursor miRNA (pre-miRNA). Differential miRNA arm selection has been reported between tumor and normal tissue in many cancer types; however, the biological function and mechanism of miRNA arm switching in gastric cancer remain unclear.
MATERIALS AND METHODS: Profiles of miRNA expression in gastric cancer were obtained from The Cancer Genome Atlas (TCGA). The biological role of miR-193a-5p/-3p in tumor growth and invasive abilities was assessed through a gain-of-function approach. Target genes of miR-193a-3p were identified using bioinformatics and an experimental approach.
RESULTS: The expression levels of miR-193a-5p, and not of miR-193a-3p, were significantly decreased in gastric cancer compared to adjacent normal tissues. Ectopic expressions of miR-193a-5p and miR-193a-3p revealed that they both inhibited gastric cancer cell growth, but only miR-193a-3p significantly suppressed cell invasion ability. Using a bioinformatics approach, we identified 18 putative target genes of miR-193a-3p. Both mRNA and protein levels of cyclin D1 (CCND1) and ETS proto-oncogene 1 (ETS1) were significantly decreased in AGS cells transfected with miR-193a-3p mimics. ETS1 or CCND1 knockdown significantly suppressed gastric cancer cell growth, similar to miR-193a-3p overexpression.
CONCLUSION: Our results indicated that miR-193a-3p suppressed gastric growth and motility, at least partly, by directly targeting CCND1 and ETS1 expression.

Motalebzadeh J, Shabani S, Rezayati S, et al.
Prognostic Value of FBXO39 and ETS-1 but not BMI-1 in Iranian Colorectal Cancer Patients
Asian Pac J Cancer Prev. 2018; 19(5):1357-1362 [PubMed] Free Access to Full Article Related Publications
Background: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Despite recent progress in diagnosis and treatment, it remains a major health problem and further studies are needed. We here investigated expression profiles of the FBXO39, ETS-1 and BMI-1 genes in CRCs to validate any possible diagnostic/prognostic significance. Material and Methods: Thirty six patients with locally advanced CRC admitted to Hazrate-Rasoul Hospital-Tehran were enrolled. Initially the expression pattern of FBXO39, ETS-1 and BMI-1 genes were determined using RT-PCR in CRC tumor and adjacent normal tissues then real-time RT-PCR was employed to quantify BMI-1 gene expression. Results: FBXO39 expression was restricted to tumor tissues. Interestingly, expression of this gene was detected in all stage-0 tumor samples. There was a significant relation between FBXO39 gene expression and lymph node involvement. The ETS-1 gene was expressed in 66% of all tumor tissues with p-value=0.03 for increase as compared to the adjacent normal samples. In addition, there was a significant relation between ETS-1 gene expression and tumor size and lymph node involvement. RT-PCR demonstrated BMI-1 gene expression in both tumor and normal tissues and quantification by real-time RT-PCR showed no association between BMI-1 levels and CRC clinicopathological features. Conclusion: Expression of FBXO39 and ETS-1 with lymph node involvement may be considered as an alarm for the occurrence of CRC metastasis, and therfore have prognostic value while BMI-1 appears without importance.

Li D, Chen Y, Mei H, et al.
Ets-1 promoter-associated noncoding RNA regulates the NONO/ERG/Ets-1 axis to drive gastric cancer progression.
Oncogene. 2018; 37(35):4871-4886 [PubMed] Free Access to Full Article Related Publications
Emerging studies have indicated the essential functions of long noncoding RNAs (lncRNAs) during cancer progression. However, whether lncRNAs contribute to the upregulation of v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1), an established oncogenic protein facilitating tumor invasion and metastasis, in gastric cancer remains elusive. Herein, we identified Ets-1 promoter-associated noncoding RNA (pancEts-1) as a novel lncRNA associated with the gastric cancer progression via mining of publicly available datasets and rapid amplification of cDNA ends. RNA pull-down, RNA immunoprecipitation, in vitro binding, and RNA electrophoretic mobility shift assays indicated the binding of pancEts-1 to non-POU domain containing octamer binding (NONO) protein. Mechanistically, pancEts-1 facilitated the physical interaction between NONO and Ets related gene (ERG), resulting in increased ERG transactivation and transcription of Ets-1 associated with gastric cancer progression. In addition, pancEts-1 facilitated the growth and aggressiveness of gastric cancer cells via interacting with NONO. In gastric cancer tissues, pancEts-1, NONO, and ERG were upregulated and significantly correlated with Ets-1 levels. High levels of pancEts-1, NONO, ERG, or Ets-1 were respectively associated with poor survival of gastric cancer patients, whereas simultaneous expression of all of them (HR = 3.012, P = 0.105) was not an independent prognostic factor for predicting clinical outcome. Overall, these results demonstrate that lncRNA pancEts-1 exhibits oncogenic properties that drive the progression of gastric cancer via regulating the NONO/ERG/Ets-1 axis.

Desterke C, Voldoire M, Bonnet ML, et al.
Experimental and integrative analyses identify an ETS1 network downstream of BCR-ABL in chronic myeloid leukemia (CML).
Exp Hematol. 2018; 64:71-83.e8 [PubMed] Related Publications
The BCR-ABL oncogene, the hallmark of chronic myeloid leukemia (CML), has been shown to activate several signaling pathways in leukemic cells. The natural history of this disease has been radically modified by tyrosine kinase inhibitors (TKIs). However, resistance to several lines of TKI therapies and progression to blast crisis (BC) remain significant concerns. To identify novel signaling pathways induced by BCR-ABL, we performed a transcriptome analysis in a BCR-ABL-expressing UT-7 cell line. More than 2000 genes differentially expressed between BCR-ABL-expressing and parental UT-7 cells were identified and ETS1 was found to be the most upregulated. ETS1 protein expression was also shown to be highly increased in UT-7 cells expressing BCR-ABL either constitutively or under the control of TET-inducible promoters. ETS1 expression is tyrosine-kinase dependent because it was reduced by TKIs. A significant increase of ETS1 messenger RNA (mRNA) expression was observed in blood cells from CML patients at diagnosis compared with healthy controls. Integration of publicly available chromatin immunoprecipitation sequencing and transcriptomic data with our results allowed us to identify potential ETS1 targets, some of which are involved in the progression of CML. The messenger RNA expression of two of these genes (DNM3 and LIMS1) was found to be associated with the absence of major cytogenetic response after 1 year of imatinib therapy. The present work demonstrates for the first time the involvement of the ETS1 transcriptional program in the experimental UT-7 model and a large cohort of CML patients.

Li Y, Gao X, Yu Z, et al.
Reversing Multidrug Resistance by Multiplexed Gene Silencing for Enhanced Breast Cancer Chemotherapy.
ACS Appl Mater Interfaces. 2018; 10(18):15461-15466 [PubMed] Related Publications
Multidrug resistance (MDR), as one of the main problems in clinical breast cancer chemotherapy, is closely related with the over expression of drug efflux transporter P-glycoprotein (P-gp). In this study, a novel drug-loaded nanosystem was developed for inhibiting the P-gp expression and reversing MDR by multiplexed gene silencing, which composes of graphene oxide (GO) modified with two molecular beacons (MBs) and Doxorubicin (Dox). When the nanosystem was uptaken by the MDR breast cancer cells, Dox was released in the acidic endosomes and MBs were hybridized with target sequences. The intracellular multidrug resistance 1 (MDR1) mRNA and upstream erythroblastosis virus E26 oncogene homolog 1 (ETS1) mRNA can be silenced by MBs, which can effectively inhibit the expression of P-gp and further prevent the efflux of Dox and reverse MDR. In vitro and in vivo studies indicated that the strategy of reversing MDR by multiplexed gene silencing could obviously increase MCF-7/Adr cells' Dox accumulation and enormously enhance the therapeutic efficacy of MDR breast cancer chemotherapy.

Kfir-Elirachman K, Ortenberg R, Vizel B, et al.
Regulation of CEACAM1 Protein Expression by the Transcription Factor ETS-1 in BRAF-Mutant Human Metastatic Melanoma Cells.
Neoplasia. 2018; 20(4):401-409 [PubMed] Free Access to Full Article Related Publications
BRAF becomes constitutively activated in 50% to 70% of melanoma cases. CEACAM1 has a dual role in melanoma, including facilitation of cell proliferation and suppression of infiltrating lymphocytes, which are consistent with its value as a marker for poor prognosis in melanoma patients. Here we show that BRAF

Peyret V, Nazar M, Martín M, et al.
Functional Toll-like Receptor 4 Overexpression in Papillary Thyroid Cancer by MAPK/ERK-Induced ETS1 Transcriptional Activity.
Mol Cancer Res. 2018; 16(5):833-845 [PubMed] Related Publications
Emerging evidence suggests that unregulated Toll-like receptor (TLR) signaling promotes tumor survival signals, thus favoring tumor progression. Here, the mechanism underlying TLR4 overexpression in papillary thyroid carcinomas (PTC) mainly harboring the BRAF

Nagy A, Bhaduri A, Shahmarvand N, et al.
Next-generation sequencing of idiopathic multicentric and unicentric Castleman disease and follicular dendritic cell sarcomas.
Blood Adv. 2018; 2(5):481-491 [PubMed] Free Access to Full Article Related Publications
Castleman disease (CD) is a rare lymphoproliferative disorder subclassified as unicentric CD (UCD) or multicentric CD (MCD) based on clinical features and the distribution of enlarged lymph nodes with characteristic histopathology. MCD can be further subtyped based on human herpes virus 8 (HHV8) infection into HHV8-associated MCD, HHV8

Mateu-Jimenez M, Curull V, Rodríguez-Fuster A, et al.
Profile of epigenetic mechanisms in lung tumors of patients with underlying chronic respiratory conditions.
Clin Epigenetics. 2018; 10:7 [PubMed] Free Access to Full Article Related Publications
Background: Chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and epigenetic events underlie lung cancer (LC) development. The study objective was that lung tumor expression levels of specific microRNAs and their downstream biomarkers may be differentially regulated in patients with and without COPD.
Methods: In lung specimens (tumor and non-tumor), microRNAs known to be involved in lung tumorigenesis (miR-21, miR-200b, miR-126, miR-451, miR-210, miR-let7c, miR-30a-30p, miR-155 and miR-let7a, qRT-PCR), DNA methylation, and downstream biomarkers were determined (qRT-PCR and immunoblotting) in 40 patients with LC (prospective study, subdivided into LC-COPD and LC,
Results: Expression of miR-21, miR-200b, miR-210, and miR-let7c and DNA methylation were greater in lung tumor specimens of LC-COPD than of LC patients. Expression of downstream markers
Conclusions: Biomarkers of mechanisms involved in tumor growth, angiogenesis, migration, and apoptosis were differentially expressed in tumors of patients with underlying respiratory disease. These findings shed light into the underlying biology of the reported greater risk to develop LC seen in patients with chronic respiratory conditions. The presence of an underlying respiratory disease should be identified in all patients with LC as the differential biological profile may help determine tumor progression and the therapeutic response. Additionally, epigenetic events offer a niche for pharmacological therapeutic targets.

Jin H, Yang L, Wang L, et al.
INPP4B promotes cell survival via SGK3 activation in NPM1-mutated leukemia.
J Exp Clin Cancer Res. 2018; 37(1):8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1) has been recognized as a distinct leukemia entity in the 2016 World Health Organization (WHO) classification. The genetic events underlying oncogenesis in NPM1-mutated AML that is characterized by a normal karyotype remain unclear. Inositol polyphosphate 4-phosphatase type II (INPP4B), a new factor in the phosphoinositide-3 kinase (PI3K) pathway-associated cancers, has been recently found a clinically relevant role in AML. However, little is known about the specific mechanistic function of INPP4B in NPM1-mutated AML.
METHODS: The INPP4B expression levels in NPM1-mutated AML primary blasts and AML OCI-AML3 cell lines were determined by qRT-PCR and western blotting. The effect of INPP4B knockdown on OCI-AML3 leukemia cell proliferation was evaluated, using the Cell Counting Kit-8 and colony formation assay. After INPP4B overexpression or knockdown, the activation of serum and glucocorticoid-regulated kinase 3 (SGK3) and AKT was assessed. The effects of PI3K signaling pathway inhibitors on the levels of p-SGK3 in OCI-AML3 cells were tested. The mass of PI (3,4) P
RESULTS: High expression of INPP4B was observed in NPM1-mutated AML. Knockdown of INPP4B repressed cell proliferation in OCI-AML3 cells, whereas recovered INPP4B rescued this inhibitory effect in vitro. Mechanically, INPP4B enhanced phosphorylated SGK3 (p-SGK3) status, but did not affect AKT activation. SGK3 was required for INPP4B-induced cell proliferation in OCI-AML3 cells. High levels of INPP4B were at least partially caused by the NPM1 mutant via ERK/Ets-1 signaling. Finally, high expression of INPP4B showed a trend towards lower overall survival and event-free survival in NPM1-mutated AML patients.
CONCLUSIONS: Our results indicate that INPP4B promotes leukemia cell survival via SGK3 activation, and INPP4B might be a potential target in the treatment of NPM1-mutated AML.

Matteucci E, Maroni P, Nicassio F, et al.
Microenvironment Stimuli HGF and Hypoxia Differently Affected miR-125b and Ets-1 Function with Opposite Effects on the Invasiveness of Bone Metastatic Cells: A Comparison with Breast Carcinoma Cells.
Int J Mol Sci. 2018; 19(1) [PubMed] Free Access to Full Article Related Publications
We examined the influence of microenvironment stimuli on molecular events relevant to the biological functions of 1833-bone metastatic clone and the parental MDA-MB231 cells. (i) In both the cell lines, hepatocyte growth factor (HGF) and the osteoblasts' biological products down regulated nuclear Ets-1-protein level in concomitance with endogenous miR-125b accumulation. In contrast, under hypoxia nuclear Ets-1 was unchanged, notwithstanding the miR-125b increase. (ii) Also, the 1833-cell invasiveness and the expression of Endothelin-1, the target gene of Ets-1/HIF-1, showed opposite patterns under HGF and hypoxia. We clarified the molecular mechanism(s) reproducing the high miR-125b levels with the mimic in 1833 cells. Under hypoxia, the miR-125b mimic maintained a basal level and functional Ets-1 protein, as testified by the elevated cell invasiveness. However, under HGF ectopic miR-125b downregulated Ets-1 protein and cell motility, likely involving an Ets-1-dominant negative form sensible to serum conditions; Ets-1-activity inhibition by HGF implicated HIF-1α accumulation, which drugged Ets-1 in the complex bound to the Endothelin-1 promoter. Altogether, 1833-cell exposure to HGF would decrease Endothelin-1 transactivation and protein expression, with the possible impairment of Endothelin-1-dependent induction of E-cadherin, and the reversion towards an invasive phenotype: this was favoured by Ets-1 overexpression, which inhibited HIF-1α expression and HIF-1 activity. (iii) In MDA-MB231 cells, HGF strongly and rapidly decreased Ets-1, hampering invasiveness and reducing Ets-1-binding to Endothelin-1 promoter; HIF-1α did not form a complex with Ets-1 and Endothelin-1-luciferase activity was unchanged. Overall, depending on the microenvironment conditions and endogenous miR-125b levels, bone-metastatic cells might switch from Ets-1-dependent motility towards colonization/growth, regulated by the balance between Ets-1 and HIF-1.

Hua S, Lei L, Deng L, et al.
miR-139-5p inhibits aerobic glycolysis, cell proliferation, migration, and invasion in hepatocellular carcinoma via a reciprocal regulatory interaction with ETS1.
Oncogene. 2018; 37(12):1624-1636 [PubMed] Related Publications
Cancer cells have metabolic features that allow them to preferentially metabolize glucose through aerobic glycolysis, providing them with a progression advantage. However, microRNA (miRNA) regulation of aerobic glycolysis in cancer cells has not been extensively investigated. We addressed this in the present study by examining the regulation of miR-139-5p on aerobic glycolysis of hepatocellular carcinoma (HCC) using clinical specimens, HCC cells, and a mouse xenograft model. We found that overexpressing miR-139-5p restrained aerobic glycolysis, suppressing proliferation, migration, and invasion in HCC cells. miR-139-5p regulated hexokinase 1 (HK1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression by directly targeting the transcription factor ETS1, which bound to the promoters of the HK1 and PFKFB3 genes. miR-139-5p-induced aerobic glycolysis, proliferation, migration, and invasion were reversed by ETS1 overexpression, while ETS1 silencing induced the expression of miR-139-5p via a post-transcriptional regulation mode involving Drosha. miR-139-5p expression was reduced in HCC compared to para-carcinoma tissue, which was confirmed in The Cancer Genome Atlas and GSE54751 HCC cohorts. Notably, the lower expression of mir-139 was correlated with worse prognosis. These outcomes indicate that reciprocal regulatory interactions between miR-139-5p and ETS1 modulate aerobic glycolysis, proliferation, and metastasis in HCC cells, suggesting new targets for HCC treatment.

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