Genomic profiling of long non-coding RNA and mRNA expression associated with acquired temozolomide resistance in glioblastoma cells

Abstract

Temozolomide (TMZ) is an alkylating chemotherapeutic agent widely used in anti-glioma treatment. However, acquired TMZ resistance represents a major clinical challenge that leads to tumor relapse or progress. This study investigated the genomic profiles including long non-coding RNA (lncRNA) and mRNA expression associated with acquired TMZ resistance in glioblastoma (GBM) cells in vitro. The TMZ-resistant (TR) of GBM sub-cell lines were established through repetitive exposure to increasing TMZ concentrations in vitro. The differentially expressed lncRNAs and mRNAs between the parental U87 and U87TR cells were detected by human lncRNA microarray method. In this study, we identified 2,692 distinct lncRNAs demonstrating >2-fold differential expression with 1,383 lncRNAs upregulated and 1,309 lncRNAs downregulated. Moreover, 4,886 differential mRNAs displayed 2,933 mRNAs upregulated and 1,953 mRNAs downregulated. Further lncRNA classification and subgroup analysis revealed the potential functions of the lncRNA-mRNA relationship associated with the acquired TMZ resistance. Gene ontology and pathway analysis on mRNAs showed significant biological regulatory genes and pathways involved in acquired TMZ resistance. Moreover, we found the ECM-receptor interaction pathway was significantly downregulated and ECM related collagen I, fibronectin, laminin and CD44 were closely associated with the TR phenotype in vitro. Our findings indicate that the dysregulated lncRNAs and mRNAs identified in this work may provide novel targets for overcoming acquired TMZ resistance in GBM chemotherapy.

Long noncoding RNA AC003092.1 promotes temozolomide chemosensitivity through miR-195/TFPI-2 signaling modulation in glioblastoma

“…Thus, genomic characterization of lncRNA alterations may provide an alternative therapeutic strategy for TMZ-resistant GB. Previously, our microarray analysis showed 2,692 lncRNAs and 2,933 mRNAs exhibiting a change of more than 2.0-fold in TMZ-resistant U87 (U87TR) cells 20 . Of note, lncRNA AC003092.1 and its nearby gene, itssue factor pathway inhibitor-2 (TFPI-2), showed a remarkable downregulation in U87TR cells when compared with its parental U87 cells (43.99 folds and 607.05 folds, respectively) 20 .…”

Fibronectin Promotes the Malignancy of Glioma Stem-Like Cells Via Modulation of Cell Adhesion, Differentiation, Proliferation and Chemoresistance

“…Increasing evidence has indicated the existence of a key population of glioblastoma cells with stem cell properties, referred to as glioma stem-like cells (GSCs; Nguyen et al, 2012 ), that are thought responsible for tumor genesis, the propagation of disease, the resistance to current chemotherapy and cancer recurrence (Filatova et al, 2013 ). Various research groups have proposed diverse hypotheses accounting for treatment failure in some patients with malignant glioma, including O 6 -methylguaninine-DNA-methytransferase gene methylation, isocitrate dehydrogenase gene mutations, aberrant ATP-binding cassette (ABC) transporter expression, p53 mutations and deletions, DNA repair deregulation, micro (mi)RNAs and long non-coding RNAs (Zeng et al, 2017 ). In addition to such concerns, the impact of the tumor microenvironment in various stem cell niches have been described in recent studies (Faissner and Reinhard, 2015 ), with several breakthroughs as a result of successfully growing stem cells on naturally-derived and synthesized substrates (Lee et al, 2012 ).…”

H19 induced by oxidative stress confers temozolomide resistance in human glioma cells via activating NF-κB signaling

“…Recently, one of the most hot targets in glioma TMZ resistance is the discovery of lncRNAs and their key roles. 31 , 32 …”

“…Constitutively activate NF-κB is a major transcription factor linked with glioma, and it may be responsible for multiple cellular functions including apoptosis inhibition and promotion of survival, invasion and immune response. 32 Activation of NF-κB signaling is also accompanied by the acquisition of TMZ resistance in glioma. 30 Our results showed that H19 knockdown inhibited NF-κB signaling as revealed by decreased NF-κB reporter activity and target expression, whereas H19 overexpression resulted in the activated NF-κB signaling.…”