Identification of Potential Serum Biomarkers of Glioblastoma: Serum Osteopontin Levels Correlate with Poor Prognosis

Abstract

Background: The aim of this study is to identify serum biomarkers with classification and prognosis utility for astrocytoma, in particular glioblastoma (GBM).Methods: Our previous glioma microarray database was mined to identify genes that encode secreted or membrane-localized proteins. Subsequent analysis was done using significant analysis of microarrays, followed by reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemical validation in tumor tissues, ELISA and Western blot validation in sera, and correlation with survival of GBM patients.Results: Significant analysis of microarrays identified 31 upregulated and 3 downregulated genes specifically in GBMs. RT-qPCR validation on an independent set of samples confirmed the GBM-specific differential expression of several genes, including three upregulated (CALU, CXCL9, and TIMP1) and two downregulated (GPX3 and TIMP3) novel genes. With respect to osteopontin (OPN), we show the GBM-specific upregulation by RT-qPCR and immunohistochemical staining of tumor tissues. Elevated serum OPN levels in GBM patients were also shown by ELISA and Western blot. GBM patients with high serum OPN levels had poorer survival than those with low serum OPN levels (median survival 9 versus 22 months respectively; P = 0.0001). Further, we also show high serum TIMP1 levels in GBM patients compared with grade II/III patients by ELISA and downregulation of serum GPX3 and TIMP3 proteins in GBMs compared with normal control by Western blot analysis.Conclusions: Several novel potential serum biomarkers of GBM are identified and validated. High serum OPN level is found as a poor prognostic indicator in GBMs.Impact: Identified serum biomarkers may have potential utility in astrocytoma classification and GBM prognosis. Cancer Epidemiol Biomarkers Prev; 19(6); 1409-22. ©2010 AACR.

p53-induced Gene 3 Mediates Cell Death Induced by Glutathione Peroxidase 3

“…However, increasing evidence suggests that GPx3 also possesses tumor suppressor activity (5,9,(22)(23)(24)(25)(26)(27)(28)(29). In this study, GPx3 carries out tumor suppressor signaling at least partly through the activation of PIG3, which is a protein associated with the generation of ROS that induces cell death.…”

Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage

“…The CSF may be the optimal body fluid to assess this issue because at least 20% is formed from intraparenchymal leakage and that modern neurosurgical techniques make chronic access relatively easy and safe. Both OPN-FL in serum and a peptide fragment of OPN in CSF have been suggested as potential markers (47,48). However, measurements of OPN-R and OPN-L, along with OPN-FL, in CSF may represent a more optimal method of monitoring tumor burden over time.…”

A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus

“…Genetic heterogeneity in GBM has been proposed to explain the limitations in the effectiveness of current therapies, which necessitates the need for prognostic gene signature (2). Many genetic and epigenetic alterations as well as expression of some genes have been correlated with poor or better prognosis (3)(4)(5)(6)(7). In addition, molecular biomarkers like methyl guanine methyl transferase (MGMT) promoter methylation, isocitrate dehydrogenase 1 (IDH1) mutation status, and Glioma-CpG Island Methylator Phenotype (G-CIMP) have been identified as GBM prognostic indicators (1,8,9).…”