Ribosomal Proteins RPS11 and RPS20, Two Stress-Response Markers of Glioblastoma Stem Cells, Are Novel Predictors of Poor Prognosis in Glioblastoma Patients

• Published in: PloS one 2015-10, Vol.10 (10), p.e0141334-e0141334
• Main Authors: Yong, William H, Shabihkhani, Maryam, Telesca, Donatello, Yang, Shuai, Tso, Jonathan L, Menjivar, Jimmy C, Wei, Bowen, Lucey, Gregory M, Mareninov, Sergey, Chen, Zugen, Liau, Linda M, Lai, Albert, Nelson, Stanley F, Cloughesy, Timothy F, Tso, Cho-Lea
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biomarkers; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; Brain cancer; Cancer; Cancer therapies; Cell Line, Tumor; Cell survival; Chemoradiotherapy; Comparative analysis; Deoxyribonucleic acid; DNA; DNA Methylation - genetics; DNA methyltransferase; DNA microarrays; Energy consumption; Fatty acids; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Genome, Human; Genomes; Glioblastoma; Glioblastoma - genetics; Glioblastoma - pathology; Glioblastomas; Glucose; Humans; Isocitrate dehydrogenase; Laboratories; Male; Medical diagnosis; Medical prognosis; Medicine; Metabolism; Methylguanine; Middle Aged; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neurosurgery; O6-methylguanine-DNA methyltransferase; Oncology; Oxidation; Oxidative stress; Pathology; Patients; Phenotype; Phenotypes; Physiological aspects; Prognosis; Proteins; Ribonucleic acid; Ribosomal protein S11; Ribosomal proteins; Ribosomal Proteins - biosynthesis; Ribosomal Proteins - genetics; RNA; Signatures; siRNA; Stem cells; Surgery; Survival; Tissue Array Analysis; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0141334

Glioblastoma stem cells (GSC) co-exhibiting a tumor-initiating capacity and a radio-chemoresistant phenotype, are a compelling cell model for explaining tumor recurrence. We have previously characterized patient-derived, treatment-resistant GSC clones (TRGC) that survived radiochemotherapy. Compared to glucose-dependent, treatment-sensitive GSC clones (TSGC), TRGC exhibited reduced glucose dependence that favor the fatty acid oxidation pathway as their energy source. Using comparative genome-wide transcriptome analysis, a series of defense signatures associated with TRGC survival were identified and verified by siRNA-based gene knockdown experiments that led to loss of cell integrity. In this study, we investigate the prognostic value of defense signatures in glioblastoma (GBM) patients using gene expression analysis with Probeset Analyzer (131 GBM) and The Cancer Genome Atlas (TCGA) data, and protein expression with a tissue microarray (50 GBM), yielding the first TRGC-derived prognostic biomarkers for GBM patients. Ribosomal protein S11 (RPS11), RPS20, individually and together, consistently predicted poor survival of newly diagnosed primary GBM tumors when overexpressed at the RNA or protein level [RPS11: Hazard Ratio (HR) = 11.5, p