|Gene:||EMP1; epithelial membrane protein 1|
|Aliases: || TMP, CL-20, EMP-1 |
|Databases:||OMIM, HGNC, Ensembl, GeneCard, Gene|
|Protein:||epithelial membrane protein 1|
|Source:||NCBIAccessed: 31 August, 2019|
What does this gene/protein do?
Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: EMP1 (cancer-related)
Echevarria MI, Awasthi S, Cheng CH, et al.African American Specific Gene Panel Predictive of Poor Prostate Cancer Outcome.
J Urol. 2019; 202(2):247-255 [PubMed
] Related Publications
PURPOSE: Most prostate cancer in African American men lacks the ETS (E26 transforming specific) family fusion event (ETS-). We aimed to establish clinically relevant biomarkers in African American men by studying ETS dependent gene expression patterns to identified race specific genes predictive of outcomes.
MATERIALS AND METHODS: Two multicenter cohorts of a total of 1,427 men were used for the discovery and validation (635 and 792 men, respectively) of race specific predictive biomarkers. We used false discovery rate adjusted q values to identify race and ETS dependent genes which were differentially expressed in African American men who experienced biochemical recurrence within 5 years. Principal component modeling along with survival analysis was done to assess the accuracy of the gene panel in predicting recurrence.
RESULTS: We identified 3,047 genes which were differentially expressed based on ETS status. Of these genes 362 were differentially expressed in a race specific manner (false discovery rate 0.025 or less). A total of 81 genes were race specific and over expressed in African American men who experienced biochemical recurrence. The final gene panel included APOD, BCL6, EMP1, MYADM, SRGN and TIMP3. These genes were associated with 5-year biochemical recurrence (HR 1.97, 95% CI 1.27-3.06, p = 0.002) and they improved the predictive accuracy of clinicopathological variables only in African American men (60-month time dependent AUC 0.72).
CONCLUSIONS: In an effort to elucidate biological features associated with prostate cancer aggressiveness in African American men we identified ETS dependent biomarkers predicting early onset biochemical recurrence only in African American men. Thus, these ETS dependent biomarkers representing ideal candidates for biomarkers of aggressive disease in this patient population.
Derkach A, Otim I, Pfeiffer RM, et al.Associations between IgG reactivity to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) antigens and Burkitt lymphoma in Ghana and Uganda case-control studies.
EBioMedicine. 2019; 39:358-368 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma linked to Plasmodium falciparum (Pf) malaria in sub-Saharan Africa. We investigated antibody reactivity to several human receptor-binding domains of the Pf erythrocyte membrane protein 1 (PfEMP1) that play a key role in malaria pathogenesis and are targets of acquired immunity to malaria.
METHODS: Serum/plasma IgG antibody reactivity was measured to 22 Pf antigens, including 18 to PfEMP1 CIDR domains between cases and controls from two populations (149 eBL cases and 150 controls from Ghana and 194 eBL cases and 600 controls from Uganda). Adjusted odds ratios (aORs) for case-control associations were estimated by logistic regression.
FINDINGS: There was stronger reactivity to the severe malaria associated CIDRα1 domains than other CIDR domains both in cases and controls. eBL cases reacted to fewer antigens than controls (Ghana: p = 0·001; Uganda: p = 0·03), with statistically significant lower ORs associated with reactivity to 13+ antigens in Ghana (aOR 0·39, 95% CI 0·24-0·63; p
INTERPRETATION: eBL cases reacted to fewer antigens than controls using samples from two populations, Ghana and Uganda. Attenuated humoral immunity to Pf EMP1 may contribute to susceptibility to low-grade malaria and eBL risk.
FUNDING: Intramural Research Program, National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services.
Tumor metastasis is the most common cause of cancer death. Elucidation of the mechanism of tumor metastasis is therefore important in the development of novel, effective anti-cancer therapies to reduce cancer mortality. Interaction between cancer cells and surrounding stromal cells in the tumor microenvironment is a key factor in tumor metastasis. Using a co-culture assay system with human prostate cancer LNCaP cells and primary human prostate stromal cells, we identified epithelial membrane protein 1 (EMP1) as a gene with elevated expression in the cancer cells. The orthotopic injection of LNCaP cells overexpressing EMP1 (EMP1-LNCaP cells) into the prostate of nude mice induced lymph node and lung metastases, while that of control LNCaP cells did not. EMP1-LNCaP cells had higher cell motility and Rac1 activity than control LNCaP cells. These results were also observed in other lines of cancer cells. We newly identified copine-III as an intracellular binding partner of EMP1. Knockdown of copine-III attenuated the increased cell motility and Rac1 activity in EMP1-LNCaP cells. Reduced cell motility and Rac1 activity following knockdown of copine-III in EMP1-LNCaP cells were recovered by re-expression of wild-type copine-III, but not of a copine-III mutant incapable of interacting with EMP1, suggesting the importance of the EMP1-copine-III interaction. Phosphorylated and activated Src and a Rac guanine nucleotide exchange factor Vav2 were found to be involved in the EMP1-induced enhancement of cell motility and Rac1 activation. Moreover, EMP1 was highly expressed in prostate cancer samples obtained from patients with higher Gleason score. These results demonstrate that upregulation of EMP1 significantly increases cancer cell migration that leads to tumor metastasis, suggesting that EMP1 may play an essential role as a positive regulator of tumor metastasis.
Purpose: Uveal melanoma (UM) is uniformly refractory to all available systemic chemotherapies, thus creating an urgent need for novel therapeutics. In this study, we investigated the sensitivity of UM cells to ICG-001, a small molecule reported to suppress the Wnt/β-catenin-mediated transcriptional program.
Methods: We used a panel of UM cell lines to examine the effects of ICG-001 on cellular proliferation, migration, and gene expression. In vivo efficacy of ICG-001 was evaluated in a UM xenograft model.
Results: ICG-001 exerted strong antiproliferative activity against UM cells, leading to cell cycle arrest, apoptosis, and inhibition of migration. Global gene expression profiling revealed strong suppression of genes associated with cell cycle proliferation, DNA replication, and G1/S transition. Gene set enrichment analysis revealed that ICG-001 suppressed Wnt, mTOR, and MAPK signaling. Strikingly, ICG-001 suppressed the expression of genes associated with UM aggressiveness, including CDH1, CITED1, EMP1, EMP3, SDCBP, and SPARC. Notably, the transcriptomic footprint of ICG-001, when applied to a UM patient dataset, was associated with better clinical outcome. Lastly, ICG-001 exerted anticancer activity against a UM tumor xenograft in mice.
Conclusions: Using in vitro and in vivo experiments, we demonstrate that ICG-001 has strong anticancer activity against UM cells and suppresses transcriptional programs critical for the cancer cell. Our results suggest that ICG-001 holds promise and should be examined further as a novel therapeutic agent for UM.
Abdalla Z, Walsh T, Thakker N, Ward CMLoss of epithelial markers is an early event in oral dysplasia and is observed within the safety margin of dysplastic and T1 OSCC biopsies.
PLoS One. 2017; 12(12):e0187449 [PubMed
] Free Access to Full Article Related Publications
Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer that is associated with poor 5-year patient survival. Disease treatment is further compounded by the difficulty in predicting pre-cancerous tissues that will progress to OSCC and the high recurrence rates following surgical resection. Here we have assessed expression of the oral epithelial markers E-cadherin, EMP1 and 5T4 and the pro-invasive N-cadherin proteins using fully characterised antibodies and quantitative immunofluorescence microscopy in normal tissue (NT), fibroepithelial polyp (FEP), low-grade dysplasia (LGD), high-grade dysplasia (HGD), T1 OSCC and T4 OSCC biopsies. Decreased E-cadherin expression was associated with FEP, LGD and HGD biopsies, demonstrating that loss of E-cadherin is an early event within abnormal epithelium and occurs in the absence of an E- to N-cadherin switch, the latter of which was only observed in T4 OSCC. Furthermore, loss of E-cadherin and EMP1 is an indicator of LGD (p = 0.0006) and loss of E-cadherin, EMP1 and 5T4 an indicator of HGD (p = 0.0006). Expression patterns of E-cadherin, EMP1 and N-cadherin could predict abnormal epithelium in LGD, HGD, T1 and T4 OSCC biopsies (z-value = 0 for all disease grades) and allowed classification of LGD (z = 1.47), HGD (z = 2.138), T1 (z = 1.05) and T4 OSCC (z = 1.49) biopsies. Therefore, these markers provide a useful means to predict abnormal epithelium in patient biopsies. Linear regression and coefficient of determination analysis revealed positive correlation with a NT>LGD>HGD disease transition but low correlation with a putative HGD>T1 OSCC>T4 OSCC disease transition. Furthermore, expression of E-cadherin, EMP1, 5T4 and N-cadherin in pathologically normal surgical safety margins of LGD, HGD and T1 OSCC patient biopsies revealed significant differences to NT and the use of safety margins or FEP as 'normal tissue' controls introduced Type II errors in all patient cohorts. This work forms the basis for further investigation of the role of E-cadherin loss in abnormal epithelium and in the development of automated analyses for use in cancer diagnostics.
BACKGROUND In the present study, we aimed to investigate the prognostic value of epithelial membrane protein 1 (EMP-1) gene in patients diagnosed with laryngeal carcinoma (LC). MATERIAL AND METHODS Patients who were pathologically diagnosed with LC were enrolled in the present study. The expression levels of EMP-1 in tumor tissues and corresponding normal tissues collected from the LC patients were detected by semi-reverse transcriptase polymerase chain reaction (semi-RT-PCR). Chi-square analysis was used to evaluate the relationship between EMP-1 expression level and clinical characteristics. Survival analysis for the study population was analyzed by Kaplan-Meier method with log rank test. Additionally, Cox regression model was applied to evaluate the prognostic value of EMP-1 in LC patients. RESULTS 106 LC patients, including 55 men and 51 women, were enrolled in the present study. Semi-RT-PCR demonstrated that the expression level of EMP-1 was decreased in tumor tissues, compared with adjacent normal tissues (p<0.001). Moreover, the level was significantly associated with lymph node metastasis, histological grade, and clinical stage (p<0.05 for all). In addition, low levels of EMP-1 was significantly correlated with poor survival rate (log rank test, p=0.020). Cox regression analysis indicated that EMP-1 was an independent marker for LC prognosis (HR=2.755, 95% CI=1.123-6.760, p=0.027). CONCLUSIONS The abnormal expression of EMP-1 may be associated with progression of LC and the gene may act as a prognostic marker for LC.
De Marco C, Laudanna C, Rinaldo N, et al.Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer.
PLoS One. 2017; 12(6):e0178865 [PubMed
] Free Access to Full Article Related Publications
Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. We found that, altogether, aberrant PI3K/AKT signalling in lung epithelial cells regulated the expression of 1,960/20,436 genes (9%), though only 30 differentially expressed genes (DEGs) (15 up-regulated, 12 down-regulated and 3 discordant) out of 20,436 that were common among BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells (0.1%). Conversely, DEGs specific for mutant AKT1 were 133 (85 up-regulated; 48 down-regulated), DEGs specific for mutant PIK3CA were 502 (280 up-regulated; 222 down-regulated) and DEGs specific for PTEN loss were 1549 (799 up-regulated, 750 down-regulated). The results obtained from array analysis were confirmed by quantitative RT-PCR on selected up- and down-regulated genes (n = 10). Treatment of BEAS-C cells and the corresponding derivatives with pharmacological inhibitors of AKT (MK2206) or PI3K (LY294002) further validated the significance of our findings. Moreover, mRNA expression of selected DEGs (SGK1, IGFBP3, PEG10, GDF15, PTGES, S100P, respectively) correlated with the activation status of the PI3K/AKT pathway assessed by S473 phosphorylation in NSCLC cell lines (n = 6). Finally, we made use of Ingenuity Pathway Analysis (IPA) to investigate the relevant BioFunctions enriched by the costitutive activation of AKT1-, PI3K- or PTEN-dependent signalling in lung epithelial cells. Expectedly, the analysis of the DEGs common to all three alterations highlighted a group of BioFunctions that included Cell Proliferation of tumor cell lines (14 DEGs), Invasion of cells (10 DEGs) and Migration of tumour cell lines (10 DEGs), with a common core of 5 genes (ATF3, CDKN1A, GDF15, HBEGF and LCN2) that likely represent downstream effectors of the pro-oncogenic activities of PI3K/AKT signalling. Conversely, IPA analysis of exclusive DEGs led to the identification of different downstream effectors that are modulated by mutant AKT1 (TGFBR2, CTSZ, EMP1), mutant PIK3CA (CCND2, CDK2, IGFBP2, TRIB1) and PTEN loss (ASNS, FHL2). These findings not only shed light on the molecular mechanisms that are activated by aberrant signalling through the PI3K/AKT pathway in lung epithelial cells, but also contribute to the identification of previously unrecognised molecules whose regulation takes part in the development of lung cancer.
Wang YW, Cheng HL, Ding YR, et al.EMP1, EMP 2, and EMP3 as novel therapeutic targets in human cancer.
Biochim Biophys Acta Rev Cancer. 2017; 1868(1):199-211 [PubMed
] Related Publications
The epithelial membrane protein genes 1, 2, and 3 (EMP1, EMP2, and EMP3) belong to the peripheral myelin protein 22-kDa (PMP22) gene family, which consists of at least seven members: PMP22, EMP1, EMP2, EMP3, PERP, brain cell membrane protein 1, and MP20. This review addresses the structural and functional features of EMPs, detailing their tissue distribution and functions in the human body, their expression pattern in a variety of tumors, and highlighting the underlying mechanisms involved in carcinogenesis. The implications in cancer biology, patient prognosis prediction, and potential application in disease therapy are discussed. For example, EMP1 was reported to be a biomarker of gefitinib resistance in lung cancer and contributes to prednisolone resistance in acute lymphoblastic leukemia patients. EMP2 functions as an oncogene in human endometrial and ovarian cancers; however, characteristics of EMP2 in urothelial cancer fulfill the criteria of a suppressor gene. Of particular interest, EMP3 overexpression in breast cancer is significantly related to strong HER-2 expression. Co-expression of HER-2 and EMP3 is the most important indicator of progression-free and metastasis-free survival for patients with urothelial carcinoma of the upper urinary tract. Altogether, discovery of pharmacological inhibitors and/or regulators of EMP protein activity could open novel strategies for enhanced therapy against EMP-mediated human diseases.
Xiaohua D, Jun Z, Huiru Z, et al.[Construction of epithelial membrane protein 1 eukaryotic expression vector and its influence on migration and invasion of human oral tongue squamous carcinoma cells].
Hua Xi Kou Qiang Yi Xue Za Zhi. 2016; 34(4):398-403 [PubMed
] Related Publications
OBJECTIVE: This study aimed to construct a eukaryotic expression vector pEGFP-N1-EMP1 of epithelial mem-brane protein 1 (EMP1) and investigate its influence on migration and invasion of human oral tongue squamous carcinoma cells.
METHODS: The human EMP1 gene was amplified by reverse transcription polymerase chain reaction and then ligated into the pEGFP-N1 vector by double restriction endonuclease digestion to construct pEGFP-N1-EMP1 recombinant plasmid. After sequencing identification, pEGFP-N1-EMP1 recombinant plasmid and pEGFP-N1 plasmid were transfected into human oral tongue squamous carcinoma Tb3.1 cell line. The expression of green fluorescent protein in cells was observed after transfection using an inverted fluorescence microscope. The overexpression of EMP1 mRNA was identified at 24, 48, and 72 h after transfection by real-time fluorescence quantitative polymerase chain reaction. The effect of EMP1 overexpression on migration and invasion of Tb3.1 cells was detected by Transwell assay.
RESULTS: The full-length EMP1 gene sequence was successfully obtained. Sequence analysis showed that the EMP1 gene was inserted into the pEGFP-N1 vector correctly. Green fluorescence was observed in the transfected cells under fluorescence microscopy. The results of real-time fluorescence quantitative polymerase chain reaction indicated that the expression of EMP1 at 24 h after pEGFP-N1-EMP1 transfection was significantly higher than the other groups. Transwell assays indicated that overexpression of the EMP1 gene could significantly inhibit the migration and invasion ability of Tb3.1 cells.
CONCLUSIONS: The eukaryotic expression vector of EMP1 was successfully constructed, and EMP1 overexpression was confirmed to inhibit the migration and inva-sion of oral tongue squamous carcinoma cells in vitro. This study laid a foundation for further investigation on the influence of the EMP1 gene on the metastasis of oral tongue squamous carcinoma and its molecular mechanism.
Genetic alterations disrupting the transcription factor
Li H, Zhang X, Jiang X, Ji XThe expression and function of epithelial membrane protein 1 in laryngeal carcinoma.
Int J Oncol. 2017; 50(1):141-148 [PubMed
] Related Publications
In this study, we compared the expression of epithelial membrane protein 1 (EMP1) on the steady-state mRNA level (by quantitative real-time PCR) and on the protein level (by western immunoblot and immunohistochemistry) in 51 pairs of laryngeal carcinoma tissues and matched cancer-free peritumor tissues, and we analyzed the correlation between EMP1 expression and different clinicopathological factors. Furthermore, we ectopically expressed EMP1 in human laryngeal carcinoma Hep-2 cells and examined the effects on cell viability, apoptosis, colonogenicity, and motility, by MTT assay, flow cytometry, colony formation assay and Transwell migration assay, respectively. EMP1 expression (on both the mRNA and protein levels) was significantly lower in the cancer tissues than in matched peritumor tissues (P<0.05). In laryngeal cancers, the level of EMP1 protein was correlated with histological grade (P<0.05), but not with age, gender, clinical stage, cancer subtype or lymph node metastasis (P>0.05). Functionally, ectopic expression of EMP1 in Hep-2 cells significantly reduced cell viability, colony formation, and migration, but enhanced apoptosis. Therefore, EMP1 is a tumor suppressor in laryngeal carcinoma. Boosting EMP1 expression in laryngeal carcinoma initiates multiple anticancer phenotypes and thus presents a promising therapeutic strategy for laryngeal cancer.
Sawanyawisuth K, Tantapotinan N, Wongkham C, et al.Suppression of trophoblast cell surface antigen 2 enhances proliferation and migration in liver fluke-associated cholangiocarcinoma.
Ann Hepatol. 2016 Jan-Feb; 15(1):71-81 [PubMed
] Related Publications
BACKGROUND AND AIM: Trophoblast cell surface antigen 2 (TROP2) or tumor-associated calcium signal transducer 2 (TACSTD2) is a 36-kDa type I transmembrane glycoprotein and exerts dual functions as an oncogene and tumor suppressor in cancer cells. In this study, we investigated the expression and functions of TROP2 in liver fluke-associated cholangiocarcinoma (CCA).
MATERIAL AND METHODS: TROP2 expression in 85 CCA tissues was detected by using immunohistochemistry. The methylation status of TROP2 promoter was studied in 15 matched pairs of normal and CCA formalin fixed paraffin embedded (FFPE) tissues using the bisulfite genomic sequencing (BGS) method. The functions of TROP2 on cancer cell behavior were investigated using siRNA in CCA cell lines. Proliferation, migration and invasion assays were performed. A PCR array was used to evaluate the impact of TROP2 knockdown on the gene expression profiles.
RESULTS: TROP2 was highly expressed in all normal bile duct epithelia, but significantly down-regulated in CCA cells. Sixty percent of CCA revealed promoter hypermethylation compared to the corresponding adjacent normal tissues. TROP2 knockdown significantly enhanced the proliferation and migration in CCA cell lines, and altered the expressions of MARCK, EMP1 and FILIP1L.
CONCLUSION: We provide new evidence that TROP2 is epigenetically down-regulated and operates as a negative regulator of cell proliferation and migration in liver fluke-associated CCA.
The GAS3 family of tetraspan proteins has recently been implicated in the progression of cancer. Currently, six members of the GAS3 family have been identified in humans and mice, and while their expressions in disease vary, data suggest that they play a role in epithelial cell structure and function. In this review, we highlight the studies implicating four of the members in disease pathogenesis as well as probe the structural similarities between the family members. Finally, the impact of targeting select members of the family such as PMP22 and EMP2 is discussed.
The human airway is lined with respiratory epithelial cells, which create a critical barrier through the formation of apical tight junctions. To investigate the molecular mechanisms underlying this process, an RNAi screen for guanine nucleotide exchange factors (GEFs) was performed in human bronchial epithelial cells (16HBE). We report that SOS1, acting through the Ras/MEK/ERK pathway, is essential for tight junction formation. Global microarray analysis identifies epithelial membrane protein 1 (EMP1), an integral tetraspan membrane protein, as a major transcriptional target. EMP1 is indispensable for tight junction formation and function in 16HBE cells and in a human airway basal progenitor-like cell line (BCi-NS1.1). Furthermore, EMP1 is significantly downregulated in human lung cancers. Together, these data identify important roles for SOS1/Ras and EMP1 in tight junction assembly during airway morphogenesis.
Peter S, Borkowska E, Drayton RM, et al.Identification of differentially expressed long noncoding RNAs in bladder cancer.
Clin Cancer Res. 2014; 20(20):5311-21 [PubMed
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PURPOSE: Loss of epigenetic gene regulation through altered long noncoding RNA (lncRNA) expression seems important in human cancer. LncRNAs have diagnostic and therapeutic potential, and offer insights into the biology disease, but little is known of their expression in urothelial cancer. Here, we identify differentially expressed lncRNAs with potential regulatory functions in urothelial cancer.
EXPERIMENTAL DESIGN: The expression of 17,112 lncRNAs and 22,074 mRNAs was determined using microarrays in 83 normal and malignant urothelial (discovery) samples and selected RNAs with qPCR in 138 samples for validation. Significantly differentially expressed RNAs were identified and stratified according to tumor phenotype. siRNA knockdown, functional assays, and whole-genome transcriptomic profiling were used to identify potential roles of selected lncRNAs.
RESULTS: We observed upregulation of many lncRNAs in urothelial cancer that was distinct to corresponding, more balanced changes for mRNAs. In general, lncRNA expression reflected disease phenotype. We identified 32 lncRNAs with potential roles in disease progression. Focusing upon a promising candidate, we implicate upregulation of AB074278 in apoptosis avoidance and the maintenance of a proproliferative state in cancer through a potential interaction with EMP1, a tumor suppressor and a negative regulator of cell proliferation.
CONCLUSIONS: We report differential expression profiles for numerous lncRNA in urothelial cancer. We identify phenotype-specific expression and a potential mechanistic target to explain this observation. Further studies are required to validate lncRNAs as prognostic biomarkers in this disease.
Sun G, Zhao G, Lu Y, et al.Association of EMP1 with gastric carcinoma invasion, survival and prognosis.
Int J Oncol. 2014; 45(3):1091-8 [PubMed
] Related Publications
The aim of this study was to determine the expression and function of epithelial membrane protein 1 (EMP1) in gastric carcinoma. Gastric samples were taken from cancer lesions and adjacent normal tissue in gastric cancer patients immediately after endoscopic biopsy. A portion of the sample was either fixed in 4% paraformaldehyde and embedded in paraffin for immunohistochemistry or stored in liquid nitrogen for western blotting. In order to determine protein expression of EMP1 in gastric cancer (n=65) and normal tissue (n=27), semi-quantitative immunohistochemistry and western blotting were utilized. For in vitro studies, the human gastric cancer cell line SGC-7901 was maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum. Recombinant lentivirus mediated overexpression of EMP1 in SGC-7901 cells was quantified with quantitative polymerase chain reaction (qPCR) and western blotting. Control SGC-7901 cells were transfected with an empty vector. To further study the effect of EMP1 overexpression in SGC-7901 cells, cell proliferation, cell apoptosis and migration and invasion assays were conducted. The expression of EMP1 was significantly lower in gastric cancer tissue compared to normal tissue using both immunohistochemistry (41.5 vs. 70.4% of tissues, P<0.05) and western blotting (0.153 ± 0.012 vs. 0.626 ± 0.058, P<0.05). Decreased expression of EMP1 was significantly correlated with tumor invasion, lymph node metastasis, clinical stage and histological grade of patients with gastric cancer (P<0.05). According to Kaplan-Meier analysis, low EMP1 expression correlated significantly with poor overall 5-year survival (47.4 vs. 70.3% survival, P<0.05). SGC-7901 cells transfected with EMP1 had a lower survival fraction, higher cell apoptosis (13.2 ± 1.5% vs. 2.2 ± 0.5%, P<0.05), significant decrease in migration and invasion (157.0 ± 16.0 and 112.0 ± 12.0, respectively vs. 243.0 ± 21.0 and 203.0 ± 19.0, respectively, P<0.05), higher caspase-9 (0.501 ± 0.050 vs. 0.114 ± 0.010, P<0.05) and lower VEGFC protein expression 0.135 ± 0.011 vs. 0.619 ± 0.074, P<0.05) relative to cells not transfected with EMP1. Low EMP1 expression in gastric cancer is associated with increased disease severity, suggesting that EMP1 may be a negative regulator of gastric cancer.
AIM: To determine the expression and function of epithelial membrane protein 1 (EMP1) in colorectal carcinoma.
METHODS: Colorectal samples were taken from cancer lesions and adjacent normal tissue in colorectal cancer patients immediately after endoscopic biopsy. A portion of the sample was either fixed in 4% paraformaldehyde and embedded in paraffin for immunohistochemistry or stored in liquid nitrogen for Western blot. In order to determine protein expression of EMP1 in colorectal cancer (n = 63) and normal tissue (n = 31), semi-quantitative immunohistochemistry and Western blot were utilized. For in vitro studies, the human colorectal cancer cell line SW-480 was maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum. Recombinant lentivirus mediated overexpression of EMP1 in SW-480 cells was quantified by real-time reverse transcription-polymerase chain reaction and Western blot. Control SW-480 cells were transfected with an empty vector. To further study the effect of EMP1 overexpression in SW-480 cells, cell proliferation, apoptosis, migration and invasion assays were conducted.
RESULTS: Expression of EMP1 was significantly lower in colorectal cancer tissue than in normal tissue using both immunohistochemistry (39.7% vs 90.3% of tissues, P < 0.05) and Western blot (0.126 ± 0.022 vs 0.632 ± 0.053, P < 0.05). The level of EMP1 protein expression was not correlated with gender, age, or tumor location. Decreased expression of EMP1 was significantly correlated with T stage, lymph node metastasis, clinic stage, and histological grade in patients with colorectal cancer (P < 0.05). According to Kaplan-Meier analysis, low EMP1 expression correlated significantly with poor overall five-year survival (34.2% vs 64.0% survival, P < 0.05). SW-480 cells transfected with EMP1 had a lower survival fraction, higher cell apoptosis (12.1% ± 1.3% vs 3.1% ± 0.6%, P < 0.05), a significant decrease in migration and invasion (124.0 ± 17.0 and 87.0 ± 12.0, respectively vs 213.0 ± 29.0 and 178.0 ± 21.0, respectively, P < 0.05), higher caspase-9 (0.635 ± 0.063 vs 0.315 ± 0.032, P < 0.05), and lower VEGFC protein expression (0.229 ± 0.021 vs 0.519 ± 0.055, P < 0.05) relative to cells not transfected with EMP1.
CONCLUSION: Low EMP1 expression in colorectal cancer is associated with increased disease severity, suggesting that EMP1 may be a negative regulator of colorectal cancer.
Ariës IM, Jerchel IS, van den Dungen RE, et al.EMP1, a novel poor prognostic factor in pediatric leukemia regulates prednisolone resistance, cell proliferation, migration and adhesion.
Leukemia. 2014; 28(9):1828-37 [PubMed
] Related Publications
Still 20% of pediatric acute lymphoblastic leukemia (ALL) patients relapse on or after current treatment strategies. Treatment failure is associated with resistance to prednisolone. We aimed to find new druggable targets that modulate prednisolone resistance. We generated microarray gene expression profiles of 256 pediatric ALL patient samples and identified a 3.4-fold increase in epithelial membrane protein 1 (EMP1) expression in in vitro prednisolone-resistant compared with -sensitive patients (P=0.003). EMP1 silencing in six precursor-B ALL (BCP-ALL) and T-ALL cell lines induced apoptosis and cell-cycle arrest leading to 84.1±4.5% reduction in survival compared with non-silencing control transduced cells (non-silencing control short hairpin, shNSC) (P=0.014). Moreover, EMP1 silencing sensitized to prednisolone up to 18.8-fold (P<0.001). EMP1 silencing also abrogated migration and adhesion to mesenchymal stromal cells (MSCs) by 78.3±9.0 and 29.3±4.1% compared with shNSC (P<0.05). We discovered that EMP1 contributes to MSC-mediated prednisolone resistance. Pathway analysis indicated that EMP1 signals through the Src kinase family. EMP1-high BCP-ALL patients showed a poorer 5-year event-free survival compared with EMP1-low patients (77±2 vs. 89±2%, P=0.003). Multivariate analysis taking along white blood cell count, age, prednisolone resistance and subtype identified EMP1 as an independent predictor for poor outcome in BCP-ALL (P=0.004, hazard ratio: 2.36 (1.31-4.25). This study provides preclinical evidence that EMP1 is an interesting candidate for drug development to optimize treatment of BCP-ALL.
Sun GG, Wang YD, Lu YF, Hu WNEMP1, a member of a new family of antiproliferative genes in breast carcinoma.
Tumour Biol. 2014; 35(4):3347-54 [PubMed
] Related Publications
This study aimed to analyze the expression, clinical significance of epithelial membrane protein 1 (EMP1) in breast carcinoma and the biological effect in its cell line by EMP1 overexpression. Immunohistochemistry and western blot were used to analyze EMP1 protein expression in 67 cases of breast cancer and 35 cases of normal tissues to study the relationship between EMP1 expression and clinical factors. Quantitative real-time RT-PCR and western blot were used to detect the mRNA level and protein of EMP1. MTT assay, migration and invasion assays were also conducted as to the influence of the upregulated expression of EMP1 that might be found on MCF-7 cell biological effect. The relative amount of EMP1 protein in breast cancer tissue was found to be significantly lower than in normal tissues (P < 0.05). The level of EMP1 protein expression was correlated with T stages, lymph node metastasis, clinic stage, and histological grade (P < 0.05). Meanwhile, loss of EMP1 expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result shown that MCF-7 cell transfected EMP1 had a lower survival fraction, higher cell apoptosis, significant decrease in migration and invasion, higher caspase-9, and lower VEGFC protein expression compared with MCF-7 cell untransfected EMP1 (P < 0.05). EMP1 expression decreased in breast cancer and correlated significantly with lymph node metastasis, clinic stage, histological grade, and poor overall survival, T stages, suggesting that EMP1 may play important roles as a negative regulator to breast cancer MCF-7 cell by regulating the expression of caspase 9 and VEGFC protein.
Sun GG, Wang YD, Cui DW, et al.EMP1 regulates caspase-9 and VEGFC expression and suppresses prostate cancer cell proliferation and invasion.
Tumour Biol. 2014; 35(4):3455-62 [PubMed
] Related Publications
This study aimed to analyze the expression, clinical significance of f epithelial membrane protejn-1 (EMP-1) in prostate carcinoma, and the biological effect in its cell line by EMP1 overexpression. Immunohistochemistry and Western blot were used to analyze EMP1 protein expression in 76 cases of prostate cancer and 34 cases of normal tissues to study the relationship between EMP1 expression and clinical factors. EMP1 lentiviral vector and empty vector were respectively transfected into prostate cancer PC-3 cell line. Quantitative real-time reverse transcription polymerase chain reaction and Western blot were used to detect the mRNA level and protein of EMP1. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, migration, and invasion assays were also conducted as to the influence of the upregulated expression of EMP1 that might be found on PC-3 cell biological effect. Immunohistochemistry: The level of EMP1 protein expression was found to be significantly lower in prostate cancer tissue than normal tissues (P < 0.05). Western blot: The relative amount of EMP1 protein in prostate cancer tissue was found to be significantly lower than in normal tissues (P < 0.05). The level of EMP1 protein expression was not correlated with age and prostate-specific antigen (PSA) concentration (P > 0.05), but it was correlated with T stages, lymph node metastasis, clinic stage, and Gleason score (P < 0.05). The result of biological function shown that PC-3 cell transfected EMP1 had a lower survival fraction, higher cell apoptosis, significant decrease in migration and invasion, higher caspase-9, and lower VEGFC protein expression compared with PC-3 cell untransfected EMP1 (P < 0.05). EMP1 expression decreased in prostate cancer and correlated significantly T stages, lymph node metastasis, clinic stage, and Gleason score, suggesting that EMP1 may play important roles as a negative regulator to prostate cancer PC-3 cell by regulating the expression of regulation of caspase-9 and VEGFC protein.
Sun GG, Lu YF, Fu ZZ, et al.EMP1 inhibits nasopharyngeal cancer cell growth and metastasis through induction apoptosis and angiogenesis.
Tumour Biol. 2014; 35(4):3185-93 [PubMed
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This study aimed to analyze the expression, clinical significance of epithelial membrane protein-1 (EMP1) in nasopharyngeal carcinoma, and the biological effect in its cell line by EMP1 overexpression. Immunohistochemistry and Western blot were used to analyze the EMP1 protein expression in 75 cases of nasopharyngeal cancer and 31 cases of normal tissues to study the relationship between EMP1 expression and clinical factors. Recombinant lentiviral vector was constructed to overexpress EMP1 and then infect nasopharyngeal cancer CNE2 cell line. Quantitative real-time RT-PCR and Western blot were used to detect the mRNA level and protein of EMP1. MTT assay, cell apoptosis, migration, and invasion assays were also conducted to determine the influence of the upregulated expression of EMP1 that might be found on CNE2 cells' biological effect. Immunohistochemistry and Western blot: The level of EMP1 protein expression was found to be significantly lower in nasopharyngeal cancer tissue than in the normal tissues (P < 0.05). Decreased expression of EMP1 was significantly correlated with T stages, lymph node metastasis, clinic stage, and histological grade of patients with nasopharyngeal cancer (P < 0.05). Meanwhile, the loss of EMP1 expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result of biological function has shown that CNE2 cell-transfected EMP1 had a lower survival fraction, higher cell apoptosis, significant decrease in migration and invasion, higher caspase-9, and lower vascular endothelial growth factor C protein expression compared with CNE2 cell-untransfected EMP1 (P < 0.05). EMP1 expression decreased in nasopharyngeal cancer and correlated significantly T stages, lymph node metastasis, clinic stage, histological grade, and poor overall survival, suggesting that EMP1 may play important roles as a negative regulator to nasopharyngeal cancer cell.
Octreotide is a widely used synthetic somatostatin analogue that significantly improves the management of neuroendocrine tumours (NETs). Octreotide acts through somatostatin receptors (SSTRs). However, the molecular mechanisms leading to successful disease control or symptom management, especially when SSTRs levels are low, are largely unknown. We provide novel insights into how octreotide controls NET cells. CNDT2.5 cells were treated from 1 day up to 16 months with octreotide and then were profiled using Affymetrix microarray analysis. Quantitative real-time PCR and western blot analyses were used to validate microarray profiling in silico data. WST-1 cell proliferation assay was applied to evaluate cell growth of CNDT2.5 cells in the presence or absence of 1 µM octreotide at different time points. Moreover, laser capture microdissected tumour cells and paraffin embedded tissue slides from SI-NETs at different stages of disease were used to identify transcriptional and translational expression. Microarrays analyses did not reveal relevant changes in SSTR expression levels. Unexpectedly, six novel genes were found to be upregulated by octreotide: annexin A1 (ANXA1), rho GTPase-activating protein 18 (ARHGAP18), epithelial membrane protein 1 (EMP1), growth/differentiation factor 15 (GDF15), TGF-beta type II receptor (TGFBR2) and tumour necrosis factor (ligand) superfamily member 15 (TNFSF15). Furthermore, these novel genes were expressed in tumour tissues at transcript and protein levels. We suggest that octreotide may use a potential novel framework to exert its beneficial effect as a drug and to convey its action on neuroendocrine cells. Thus, six novel genes may regulate cell growth and differentiation in normal and tumour neuroendocrine cells and have a role in a novel octreotide mechanism system.
Koch M, Wiese MGene expression signatures of angiocidin and darapladib treatment connect to therapy options in cervical cancer.
J Cancer Res Clin Oncol. 2013; 139(2):259-67 [PubMed
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PURPOSE: To assign functional properties to gene expression profiles of cervical cancer stages and identify clinically relevant biomarker genes.
EXPERIMENTAL DESIGN: Microarray samples of 24 normal and 102 cervical cancer biopsies from four publicly available studies were pooled and evaluated. High-quality microarrays were normalized using the CONOR package from the Bioconductor project. Gene expression profiling was performed using variance-component analysis for accessing most reliable probes, which were subsequently processed by gene set enrichment analysis.
RESULTS: Of 22.277 probes that were subject to variance-component analysis, eleven probes had low heterogeneity, that is, a W/T ratio between 0.18 and 0.38. Seven of these probes are induced in all cervical cancer stages: they are GINS1, PAK2, DTL, AURKA, PRKDC, NEK2 and CEP55. The other four probes are induced in normal cervix: P11, EMP1, UPK1A and HSPC159. We performed GSEA of 9.873 probes exhibiting less variability, that is, having a W/T ratio of <0.75. Repeatedly, significant gene expression signatures were found that are related to treatment using angiocidin and darapladib. Additionally, expression signatures from immunological disease signatures were found, for example graft versus host disease and acute kidney rejection. Another finding comprises a gene expression signature in stage IB2 that refers to MT1-MMP-dependent migration and invasion. This gene signature is accompanied by gene expression signatures which refer to ECM receptor-mediated interactions.
CONCLUSION: Analysis of cervical cancer patient gene expression data reveals a novel perspective on HPV-mediated transcription processes. This novel point of view contains a better understanding and even might provide improvements to cancer therapy.
Zhang T, Wang Q, Zhao D, et al.The oncogenetic role of microRNA-31 as a potential biomarker in oesophageal squamous cell carcinoma.
Clin Sci (Lond). 2011; 121(10):437-47 [PubMed
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miR-31 (microRNA-31) is frequently altered in numerous cancers. The aim of the present study was to investigate the role of miR-31 in ESCC (oesophageal squamous cell carcinoma). We measured miR-31 in 45 paired ESCC tissues and 523 serum samples using real-time RT (reverse transcription)-PCR. The serum samples were divided into a discovery group (120 ESCCs and 121 normal controls), a validation group (81 ESCCs and 81 controls), and a final group comprising six other common tumours (colorectal, liver, cervical, breast, gastric and lung cancers; total n=120). A Mann-Whitney U test and Wilcoxon matched-pairs test were used for the statistics. miR-31 was up-regulated in 77.8% of the ESCC tissues. Serum miR-31 levels in ESCC patients were significantly higher than in normal controls (P<0.001). It yielded an ROC (receiver operating characteristic) AUC (area under the curve) of 0.902 [95% CI (confidence interval), 0.857-0.936] in the discovery group and a similar result in the validation group [ROC AUC, 0.888 (95% CI, 0.819-0.939)]. Patients with high-levels of serum miR-31 also had a poorer prognosis in relapse-free survival (P=0.001) and tumour-specific survival (P=0.005). In vitro studies showed that miR-31 promoted ESCC colony formation, migration and invasion. Luciferase reporter and Western blot assays confirmed that three tumour suppressor genes, namely EMP1 (epithelial membrane protein 1), KSR2 (kinase suppressor of ras 2) and RGS4 (regulator of G-protein signalling 4), were targeted by miR-31. We conclude that miR-31 plays oncogenetic functions and can serve as a potential diagnostic and prognostic biomarker for ESCC.
Zhang J, Cao W, Xu Q, Chen WTThe expression of EMP1 is downregulated in oral squamous cell carcinoma and possibly associated with tumour metastasis.
J Clin Pathol. 2011; 64(1):25-9 [PubMed
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AIMS: To investigate the expression of EMP1 in oral squamous cell carcinoma (OSCC) tissues and its correlation with available clinical parameters of patients with OSCC.
METHODS: The mRNA levels of EMP1 were measured in 18 paired OSCC and corresponding adjacent normal tissues using RT-PCR. Another 45 pairs of OSCC samples were selected to detect the mRNA level of EMP1 using quantitative RT-PCR (qRT-PCR). The protein levels of EMP1 were also evaluated in 60 cases of patients with OSCC using immunohistochemical staining. The correlation between EMP1 expression and clinical parameters was analysed with non-parametric analysis.
RESULTS: The results of RT-PCR and qRT-PCR showed that, compared with the paired normal tissues, the mRNA levels of EMP1 were significantly decreased in OSCC. The immunohistochemical results indicated that the EMP1 protein was also downregulated in OSCC (p=0.031). Decreased expression of EMP1 was significantly correlated with clinical stage (p=0.002) and lymph node metastasis (p=0.044) of patients with OSCC. Meanwhile, there was a significant difference between OSCCs at early and advanced stages (p=0.003), and between OSCCs with lymph node metastasis and no lymph node metastasis (p=0.045), respectively.
CONCLUSIONS: The results suggest that EMP1 may be a tumour suppressor and associated with lymph node metastasis in OSCC.
Epidermal growth factor receptor (EGFR) plays a critical role in oncogenesis, which makes it an attractive target for pharmacologic inhibition. Yet, EGFR inhibition with tyrosine kinase inhibitors (TKI) does not result in a measurable and sustainable clinical benefit in a vast majority of tumors. This emphasizes the need for further investigations into resistance mechanisms against EGFR-TKIs. We previously reported the generation of an in vivo adenocarcinoma model of EGFR-TKI-acquired resistance that was devoid of the known mechanisms of resistance. Using this same xenograft model, we now show that the tumor stroma plays an important role in limiting responsiveness to EGFR-TKIs. EGFR-TKI-resistant tumors display increased surface expression of CD44(hi)/CD24(lo) and markers of epithelial to mesenchymal transition (EMT), SNAI1, and N-cadherin. An in vivo green fluorescent protein-tagging approach reveals that the tumor stroma of the EGFR-TKI-resistant tumors is distinct in that 24% of its cancer-associated fibroblast (CAF) population is composed of EMT-derived tumor cells that represent the in vivo escape from EGFR-TKIs. We further show that EMT subpopulation-harboring CAFs isolated from the EGFR-TKI-resistant tumors are tumorigenic and express the biomarker of gefitinib resistance, epithelial membrane protein-1. Finally, we provide evidence that paracrine factors secreted from the EGFR-TKI-resistant CAFs mitigate the EGFR-TKI-mediated blockade of pEGFR and pMAPK in cocultured tumor cells, regardless of their EGFR mutational status. This is the first demonstration that the tumor stroma is modified with acquisition of EGFR-TKI resistance and that it further contributes in promoting drug resistance.
Yin HF, Li T, Zhang H, Zhang S[Differential diagnosis of invasive ductal carcinoma versus invasive lobular carcinoma of breast].
Zhonghua Bing Li Xue Za Zhi. 2009; 38(10):663-7 [PubMed
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OBJECTIVE: To study the diagnostic usefulness of immunohistochemical markers in distinguishing between invasive ductal carcinoma and invasive lobular carcinoma of breast.
METHODS: Twenty-four cases of grade I invasive ductal carcinoma, 12 cases of classic invasive lobular carcinoma and 14 cases of invasive carcinoma with mixed ductal and lobular features were retrieved from the archival files of Peking University First Hospital during the period from January, 1998 to December, 2001. Immunohistochemical study for E-cadherin, p120 catenin, epithelia membrane protein 1 (EMP1) and DVL1 was performed.
RESULTS: The positivity rates for E-cadherin in grade I invasive ductal carcinoma and classic invasive lobular carcinoma were 83.3% (20/24) and 0, respectively (P < 0.01). The positivity rates for p120 catenin were 100% in both grade 1 invasive ductal carcinoma (membranous staining) and classic invasive lobular carcinoma (cytoplasmic staining). The positivity rates for EMP1 and DVL1 in gradeI invasive ductal carcinoma were 95.8% (23/24) and 54.2% (13/24), respectively; while those in classic invasive lobular carcinoma were 12 and 5 cases, respectively.
CONCLUSIONS: E-cadherin and p120 catenin are useful immunomarkers for distinguishing between invasive ductal carcinoma and invasive lobular carcinoma. On the other hand, EMP1 and DVL1 are of limited value in this respect.
Zinovyeva MV, Monastyrskaya GS, Kopantzev EP, et al.Identification of some human genes oppositely regulated during esophageal squamous cell carcinoma formation and human embryonic esophagus development.
Dis Esophagus. 2010; 23(3):260-70 [PubMed
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Here we directly compared gene expression profiles in human esophageal squamous cell carcinomas and in human fetal esophagus development. We used the suppression subtractive hybridization technique to subtract cDNAs prepared from tumor and normal human esophageal samples. cDNA sequencing and reverse transcription polymerase chain reaction (RT-PCR) analysis of RNAs from human tumor and the normal esophagus revealed 10 differentially transcribed genes: CSTA, CRNN, CEACAM1, MAL, EMP1, ECRG2, and SPRR downregulated, and PLAUR, SFRP4, and secreted protein that is acidic and rich in cysteine upregulated in tumor tissue as compared with surrounding normal tissue. In turn, genes up- and downregulated in tumor tissue were down- and upregulated, respectively, during development from the fetal to adult esophagus. Thus, we demonstrated that, as reported for other tumors, gene transcriptional activation and/or suppression events in esophageal tumor progression were opposite to those observed during development from the fetal to adult esophagus. This tumor 'embryonization' supports the idea that stem or progenitor cells are implicated in esophageal cancer emergence.
Zhou YB, Huang ZX, Ren CP, et al.[Screening and preliminary analysis of the apoptosis- and proliferation-related genes in nasopharyngeal carcinoma].
Nan Fang Yi Ke Da Xue Xue Bao. 2009; 29(4):645-7 [PubMed
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UNLABELLED: To screen and analyze the apoptosis- and proliferation-related genes in human nasopharyngeal carcinoma (NPC).
METHODS: According to gene ontology classification, the abnormal expressions of the genes related to cell apoptosis and proliferation were identified in the NPC gene chip data. The cell apoptosis- and proliferation-related genes expressed in each of the 3 stages, as defined by the tree model for the pathogenesis and progression of NPC, were screened, and with literature review, their distribution in the tree model were analyzed.
RESULTS: Nineteen genes related to cell apoptosis were found in NPC, among which 9 were down-regulated (such as DNASE1L3) and located in the chromosome deletion regions, and 10 were up-regulated (such as DEDD) in the chromosome amplification regions. Twenty-one cell proliferation-related genes were identified, including 8 down-regulated genes (such as TUSC2) in the chromosome deletion regions and 13 up-regulated ones (such as EMP1) in the chromosome amplification regions. In the chromosome deletion regions, the down-regulated cell apoptosis-related genes participated mostly in inducing and regulating cell apoptosis, and the up-regulated cell proliferation-related genes in the chromosome amplification regions were mostly associated with the positive regulation of cell proliferation.
CONCLUSION: NPC occurs possibly through two pathways by inhibiting cell apoptosis or by promoting excessive cell proliferation.
Ewing tumors (ET) are highly malignant, localized in bone or soft tissue, and are molecularly defined by ews/ets translocations. DNA microarray analysis revealed a relationship of ET to both endothelium and fetal neural crest. We identified expression of histone methyltransferase enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be increased in ET. Suppressive activity of EZH2 maintains stemness in normal and malignant cells. Here, we found EWS/FLI1 bound to the EZH2 promoter in vivo, and induced EZH2 expression in ET and mesenchymal stem cells. Down-regulation of EZH2 by RNA interference in ET suppressed oncogenic transformation by inhibiting clonogenicity in vitro. Similarly, tumor development and metastasis was suppressed in immunodeficient Rag2(-/-)gamma(C)(-/-) mice. EZH2-mediated gene silencing was shown to be dependent on histone deacetylase (HDAC) activity. Subsequent microarray analysis of EZH2 knock down, HDAC-inhibitor treatment and confirmation in independent assays revealed an undifferentiated phenotype maintained by EZH2 in ET. EZH2 regulated stemness genes such as nerve growth factor receptor (NGFR), as well as genes involved in neuroectodermal and endothelial differentiation (EMP1, EPHB2, GFAP, and GAP43). These data suggest that EZH2 might have a central role in ET pathology by shaping the oncogenicity and stem cell phenotype of this tumor.