MICRORNA ANALYSIS OF THE INVASIVE MARGIN OF GLIOBLASTOMA REVEALS DRUGGABLE THERAPEUTIC TARGETS IN LIPID METABOLISM PATHWAYS. (3rd October 2018)

• Record Type: Journal Article
• Authors: Alfardus, Huda; de los Angeles Estevez Cebrero, Maria; Rowlinson, Jonathan; Lourdusamy, Anbarasu; Grundy, Richard; Mcintyre, Alan; Smith, Stuart
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 5
• Page Start: v348
• Page End: v348
• Publication Date: 2018-10-03
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy129.019
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Heterogeneity of gene expression in Glioblastoma (GBM) has been recently recognised as a key feature involved in therapy resistance with invasive cells remaining after surgery and displaying unique molecular features. The dysregulation of small non-coding RNAs known as microRNAs (miRNAs) can disrupt gene regulatory networks and contribute to GBM development. However, the intra-tumour heterogeneity of miRNA expression in GBM has not yet been investigated. Here, we conducted microarray analysis using surgical specimens (n=72) sampled from the tumour necrotic core, proliferative rim and the invasive margin to show that different regions of the GBM tumour possess different miRNA expression profiles. We identified and validated two significantly upregulated miRNAs in the invasive margin compared to the core and the rim of the tumour. Functional studies using individual or combined overexpression of the two candidate miRNAs revealed that these miRNAs may act synergistically to target key enzymes involved in fatty acid oxidation (ACOX1 and CPT2) and lipoprotein uptake and secretion (LDLR). The expression of these gene targets was analysed in tumour samples by real-time quantitative polymerase chain reaction, flow cytometry and immunohistochemistry. These metabolic pathways will be further confirmed by liquid chromatography coupled with electrospray mass spectrometry (LC-ESI-MS). Our finding indicates that lipid metabolism may present a possible vulnerability of GBM invasive margin; indeed, pharmacological inhibition of CPT2 slowed the growth of patient-derived GBM cells. Understanding the function of miRNAs in regulating lipid homeostasis in GBM may provide novel avenues for GBM therapy.