Ribosomal Proteins RPS11 and RPS20, Two Stress-Response Markers of Glioblastoma Stem Cells, Are Novel Predictors of Poor Prognosis in Glioblastoma Patients.
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<0.001; RPS20: HR = 4.5, p = 0.03; RPS11+RPS20: HR = 17.99, p = 0.001]. The prognostic significance of RPS11 and RPS20 was further supported by whole tissue section RPS11 immunostaining (27 GBM; HR = 4.05, p = 0.01) and TCGA gene expression data (578 primary GBM; RPS11: HR = 1.19, p = 0.06; RPS20: HR = 1.25, p = 0.02; RPS11+RPS20: HR = 1.43, p = 0.01). Moreover, tumors that exhibited unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) or wild-type isocitrate dehydrogenase 1 (IDH1) were associated with higher RPS11 expression levels [corr (IDH1, RPS11) = 0.64, p = 0.03); [corr (MGMT, RPS11) = 0.52, p = 0.04]. These data indicate that increased expression of RPS11 and RPS20 predicts shorter patient survival. The study also suggests that TRGC are clinically relevant cells that represent resistant tumorigenic clones from patient tumors and that their properties, at least in part, are reflected in poor-prognosis GBM. The screening of TRGC signatures may represent a novel alternative strategy for identifying new prognostic biomarkers.
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
William H
WH
Yong
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Maryam
M
Shabihkhani
Department of Biostatistics, University of California Los Angeles, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
Donatello
D
Telesca
Department of Neurosurgery, General Hospital of Guangzhou Military Command, Guangzhou, China; Department of Surgery/Surgical-Oncology, University of California Los Angeles, Los Angeles, California, United States of America; Department of Neurosurgery, University of California Los Angeles, Los Angeles, California, United States of America.
Shuai
S
Yang
Department of Surgery/Surgical-Oncology, University of California Los Angeles, Los Angeles, California, United States of America.
Jonathan L
JL
Tso
Department of Surgery/Surgical-Oncology, University of California Los Angeles, Los Angeles, California, United States of America.
Jimmy C
JC
Menjivar
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Bowen
B
Wei
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Gregory M
GM
Lucey
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Sergey
S
Mareninov
Department of Human Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
Zugen
Z
Chen
Department of Neurosurgery, University of California Los Angeles, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
Linda M
LM
Liau
Department of Neurology/Neuro-Oncology, University of California Los Angeles, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
Albert
A
Lai
Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, United States of America; Department of Human Genetics, University of California Los Angeles, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
Stanley F
SF
Nelson
Department of Neurology/Neuro-Oncology, University of California Los Angeles, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
Timothy F
TF
Cloughesy
Department of Surgery/Surgical-Oncology, University of California Los Angeles, Los Angeles, California, United States of America; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
Cho-Lea
CL
Tso
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D012269:Ribosomal Proteins / Q000096:biosynthesis* / Q000235:genetics; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; C402488:RPS11 protein, human; D012269:Ribosomal Proteins; C029611:ribosomal protein S20