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ELTD1, a potential new biomarker for gliomas.

ABSTRACT: BACKGROUND:Glioblastoma multiforme (GBM), a high-grade glioma, is characterized by being diffuse, invasive, and highly angiogenic and has a very poor prognosis. Identification of new biomarkers could help in the further diagnosis of GBM. OBJECTIVE:To identify ELTD1 (epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1) as a putative glioma-associated marker via a bioinformatic method. METHODS:We used advanced data mining and a novel bioinformatics method to predict ELTD1 as a potential novel biomarker that is associated with gliomas. Validation was done with immunohistochemistry, which was used to detect levels of ELTD1 in human high-grade gliomas and rat F98 glioma tumors. In vivo levels of ELTD1 in rat F98 gliomas were assessed using molecular magnetic resonance imaging. RESULTS:ELTD1 was found to be significantly higher (P = .03) in high-grade gliomas (50 patients) compared with low-grade gliomas (21 patients) and compared well with traditional immunohistochemistry markers including vascular endothelial growth factor, glucose transporter 1, carbonic anhydrase IX, and hypoxia-inducible factor 1?. ELTD1 gene expression indicates an association with grade, survival across grade, and an increase in the mesenchymal subtype. Significantly high (P < .001) in vivo levels of ELTD1 were additionally found in F98 tumors compared with normal brain tissue. CONCLUSION:Results of this study strongly suggests that associative analysis was able to accurately identify ELTD1 as a putative glioma-associated biomarker. The detection of ELTD1 was also validated in both rodent and human gliomas and may serve as an additional biomarker for gliomas in preclinical and clinical diagnosis of gliomas.

SUBMITTER: Towner RA

PROVIDER: S-EPMC3555701 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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ELTD1, a potential new biomarker for gliomas.

Towner Rheal A RA Jensen Randy L RL Colman Howard H Vaillant Brian B Smith Nataliya N Casteel Rebba R Saunders Debra D Gillespie David L DL Silasi-Mansat Robert R Lupu Florea F Giles Cory B CB Wren Jonathan D JD

Neurosurgery 20130101 1

<h4>Background</h4>Glioblastoma multiforme (GBM), a high-grade glioma, is characterized by being diffuse, invasive, and highly angiogenic and has a very poor prognosis. Identification of new biomarkers could help in the further diagnosis of GBM.<h4>Objective</h4>To identify ELTD1 (epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1) as a putative glioma-associated marker via a bioinformatic method.<h4>Methods</h4>We used advanced data mining and ...[more]

PMID: 23096411

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Project description:BackgroundGlioma is the most common primary malignant tumor in the central nervous system. Myeloid differentiation protein 2 (MD2) acts as a coreceptor of toll-like receptor 4 (TLR4) to mediate innate immune response. However, the actual roles of MD2 in the regulation of progression and immune cell infiltration in gliomas remain largely unclear. This study aims to explore whether MD2 could be an independent prognostic factor through the mediation of immune cell infiltration in gliomas.MethodsThe mRNA expression and DNA methylation differential analyses of MD2 were performed using CGGA, TCGA and Rembrandt databases and survival analyses were performed using Kaplan-Meier plotter. Univariate and multivariate Cox regression was applied to analyze the prognostic value of MD2 and nomograms were constructed to evaluate the clinical value of MD2. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were utilized to analyze MD2-related signal pathways. Furthermore, correlations between MD2 and immune cell infiltration were calculated by TIMER and CIBERSOPT. The correlation between MD2 expression and the infiltrations of macrophages and neutrophils was experimentally verified by the knockdown of MD2 expression using small interfering RNA (siRNA) in glioma cells.ResultsWe found that MD2 was overexpressed and associated with a poor prognosis in gliomas. Meanwhile, higher expression of MD2 could be a result of lower DNA methylation of MD2 gene in gliomas. In addition, univariate and multivariate Cox regression analysis indicated that MD2 could be an independent prognostic factor for gliomas. Further functional enrichment analysis revealed that the functions of MD2 were closely related to immune responses. Moreover, the expression level of MD2 was strongly correlated with the infiltration and polarization of pro-tumor phenotype of tumor-associated macrophages and tumor-associated neutrophils in gliomas.ConclusionsThese findings have provided strong evidence that MD2 could be served as a valuable immune-related biomarker to diagnose and predict the progression of gliomas.

Project description:BackgroundGlioma is the most common primary malignant central nervous system tumor in adult, and is usually not curable due to its invasive nature. Establishment of serum biomarkers for glioma would be beneficial both for early diagnosis and adequate therapeutic intervention. Filamins are an actin cross-linker and filamin C (FLNC), normally restricted in muscle tissues, offers many signaling molecules an essential communication fields. Recently, filamins have been considered important for tumorigenesis in cancers.MethodsWe searched for novel glioma-associated antigens by serological identification of antigens utilizing recombinant cDNA expression cloning (SEREX), and found FLNC as a candidate protein. Tissue expressions of FLNC (both in normal and tumor tissues) were examined by immunohistochemistry and quantitative RT-PCR analyses. Serum anti-FLNC autoantibody level was measured by ELISA in normal volunteers and in the patients with various grade gliomas.ResultsFLNC was expressed in glioma tissues and its level got higher as tumor grade advanced. Anti-FLNC autoantibody was also detected in the serum of glioma patients, but its levels were inversely correlated with the tissue expression. Serum anti-FLNC autoantibody level was significantly higher in low-grade glioma patients than in high-grade glioma patients or in normal volunteers, which was confirmed in an independent validation set of patients' sera. The autoantibody levels in the patients with meningioma or cerebral infarction were at the same level of normal volunteers, and they were significantly lower than that of low-grade gliomas. Total IgG and anti-glutatione S-transferase (GST) antibody level were not altered among the patient groups, which suggest that the autoantibody response was specific for FLNC.ConclusionsThe present results suggest that serum anti-FLNC autoantibody can be a potential serum biomarker for early diagnosis of low-grade gliomas while it needs a large-scale clinical study.

Project description:BackgroundPrognosis for pediatric metastatic Retinoblastoma (Rb) is poor and current therapies are limited by high systemic toxicity rates and insufficient therapeutic efficacy for metastatic Rb. Tumor dissemination to the brain is promoted by the heterogeneous adhesive and invasive properties of Rb cells within the tumor. In this study we evaluate, for the first time, the expression, and roles of the ELTD1 and GPR125 adhesion G protein-coupled receptors (GPCRs) in Rb cell migration, viability and invasion.MethodsWe characterized the RNA expression of adhesion-GPCRs in 64 Rb tumors compared to 11 fetal retinas using the database from the Childhood Solid Tumor Network from St Jude Children's Research Hospital. The role of ELTD1 and GPR125 in Rb were investigated ex vivo by microarray analysis, in vitro by cell viability, Western blot and migration assays, in addition to imaging of the subcellular localization of the GPCRs. To elucidate their role in vivo we utilized siRNA technology in an established Rb orthotopic xenograft murine model.ResultsOur investigation demonstrates, for the first time, that ELTD1 but not GPR125, is significantly increased in Rb tumors compared to fetal retinas. We utilized established the Rb cell lines Y79 and Weri-Rb-1, which represent an aggressive, metastatic, and non-metastatic phenotype, respectively, for the in vitro analyses. The studies demonstrated that ELTD1 is enriched in Weri-Rb-1 cells, while GPR125 is enriched in Y79 cells. The measured differences extended to their subcellular localization as ELTD1 labeling displayed punctate clusters in cell-to-cell adhesion sites of Weri-Rb-1 cells, while GPR125 displayed a polarized distribution in Y79 cells. Lastly, we demonstrated the lack of both adhesion receptors does not affect Rb cell viability, yet inhibition of ELTD1 decreases Y79 cell migration in vitro and invasion in vivo.ConclusionTaken together, our data suggest that ELTD1, is a potential target to prevent extraocular Rb. The results within establish ELTD1 as a potential therapeutic target for metastatic Rb.

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ELTD1, a potential new biomarker for gliomas.

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ELTD1, a potential new biomarker for gliomas.

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